ZA200304945B - Heterocyclic compounds having antibacterial activity, process for their preparation and pharmaceutical compositions containing them. - Google Patents
Heterocyclic compounds having antibacterial activity, process for their preparation and pharmaceutical compositions containing them. Download PDFInfo
- Publication number
- ZA200304945B ZA200304945B ZA200304945A ZA200304945A ZA200304945B ZA 200304945 B ZA200304945 B ZA 200304945B ZA 200304945 A ZA200304945 A ZA 200304945A ZA 200304945 A ZA200304945 A ZA 200304945A ZA 200304945 B ZA200304945 B ZA 200304945B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- salts
- oxazolan
- phenyl
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 34
- 238000002360 preparation method Methods 0.000 title claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 13
- 230000000844 anti-bacterial effect Effects 0.000 title description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
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- -1 pyrrolidinylthiocarbonyl Chemical group 0.000 claims description 116
- 229910052739 hydrogen Inorganic materials 0.000 claims description 109
- 125000003545 alkoxy group Chemical group 0.000 claims description 108
- 239000001257 hydrogen Substances 0.000 claims description 106
- 125000005843 halogen group Chemical group 0.000 claims description 95
- 125000003118 aryl group Chemical group 0.000 claims description 78
- 150000002431 hydrogen Chemical class 0.000 claims description 74
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 69
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
- 125000003282 alkyl amino group Chemical group 0.000 claims description 51
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 51
- 125000004104 aryloxy group Chemical group 0.000 claims description 50
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 34
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 33
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
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- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
HETEROCYCLIC COMPOUNDS HAVING ANTIBACTERIAL ACTIVITY, PROCESS FOR THEIR ) PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to novel oxazolidinone compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them. More particularly, the present invention relates to novel oxazolidinones of the general formula (I).
Y2 x 1
Anh 0 ®
YY [ (x their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
The present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them. ~ The present invention also relates to novel intermediates, methods for their preparation and their use in the preparation of compounds of formula (I). : Oxazolidinones are useful as antibacterials (J. Med. Chem., 1996, 39, 673), antihistamines and anti allergic agents (EP 291,244), anticonvulsants (DE 3,915,184), treating cognition disorders, anti psychotics, anti platelet aggregators, antidepressants, sedatives, hypnotics, monoamine oxidase inhibitors (WO 97/13768) and as chiral auxiliaries (Aldrichimica Acta, 1982, 15 23) in asymmetric synthesis.
Since the discovery of penicillin, pharmaceutical companies have produced more than one hundred antibacterial agents to combat a wide variety of bacterial infections. In ) the past several years, due to the misuse of these antibiotics there has been rapid , emergence of bacterial resistance to several of these antibiotics. The multidrug resistance among these bacterial pathogens may also be due to mutation leading to more virulent clinical isolation, the most disturbing milestone has been the acquisition of resistance to vancomycin, an antibiotic generally regarded as the agent of last resort for serious Gram-positive infections. This growing multidrug resistance has recently rekindled interest in the search for new structural class of antibiotic that inhibit or kill these bacteria possibly by novel mechanisms.
A problem of larger dimension is the increasing incidence of the more’ virulent, methicillin-resistant Staphylococcus aureas (MRSA) among clinical isolates found worldwide. As with vancomycin resistant organisms, many MRSA strains are resistant to most of the known antibiotics, but MRSA strains have remained sensitive to vancomycin. However, in view of the increasing reports of vancomycin resistant clinical isolates and growing problem of ‘bacterial resistance, there is an urgent need for new molecular entities effective against the emerging and currently problematic Gram- positive organisms.
Recently, several oxazolidinones have been discovered, which inhibit protein - synthesis by binding to the 50S-ribosomal subunit which is close to the site to which chloramphenicol and lincomycin bind but their mode of action is mechanistically distinct from these two antibiotics. ’
The new class of oxazolidinones of the present invention is useful for the treatment of a number of resistant and sensitive gram-positive strains both in vitro and in vivo. Some of the hitherto known compounds described in the prior art are outlined a below: ) 6) International Patent Application WO 93/23384 discloses compounds of formula ) (IIa) .
z u 0
CH, = Ao oo . X Vv w . where Y represents a hydrogen atom, (C;-Cg)alkyl or aryl, OH, O(C-Ce)alkyl, O-vinyl,
O-phenyl, O-C(=0)(C;-Cs)alkyl, -O-C(=0)-phenyl (phenyl can be substituted with one to three F, Cl, OCHs, OH, NH, or (C,-Cs)alkyl) or O-C(=0)-O-CHj, S(C,-Coalkyl, 80z(Ci-Co)alkyl, -SO-NR’),, (where R? is independently hydrogen, (C,-C,)alkyl or phenyl which can be substituted with one to three F, Cl, OCH,, OH, NH,, or (Cy
Cy)alkyl); : -C(=0)-(C1-Co)alkyl, -C(=0)-0-(Ci-Co)alkyl, -C(=0)-N(R’),, -C(=0)-CHR)NR’), -
C(=0)-CH(R*)-NH-C(NH)-NH; (where R* is an amino acid side chain); -N(R?),, -
N(CHz)m (where m is 2-6 and forms a cyclic structure with the nitrogen atom and where one or more carbon atoms can be replaced with S, O or NR), -C(CH3)=N-OR or Y represents any of the groups given below : 0) — Hx, J x) ; Lone ; ig 0 0 —C(O)— or; — oN Re——/ \ I~ o. © ; Pe g - Rg $C) YY (0) where R’ is OH, OCH3;, CH,OH, CH,0CH;, CO,CH;, CO,CHs, R® represents CH; or hydrogen, R’ represents CH, or C(=0), R® represents hydrogen or =0, p is1or2 R’ represents O, S, S(O), SO;, CH,, NH, NCHj;, NC;Hs, NCHO, NCOCH; or NCO,CH;, wherein each occurrence of said (C,-Cs)alkyl may be substituted with one or more F, Cl,
Br, I, OR', COOR', CN, SR' or R' (where R' is a hydrogen or (C;-Cy)alkyl); X and Z are independently (C;-Cg)alkyl, (C3-C)z)cycloalkyl or hydrogen or X and Z form a (Co- C,) bridging group, preferably X and Z are hydrogen; U, V and W are independently . (C-C¢)alkyl, F, Cl, Br, hydrogen or a (C;-Cy)alkyl substituted with one or more of F, Cl,
Br or |, preferably U and V are F and W is hydrogen; R is hydrogen, (C;-Cjz)alkyl, (Cs-
Ciz)eycloalkyl, (Ci-Ce)alkoxy, (Ci-Cg)alky! substituted with one or more F , CL Br, 1or
OH ,nis 1 or 2; and q is 0-4 inclusive.
An example of this class of compounds is shown in formula (IIb) ] . 0 0 . mo Sy (Ib)
F
(i) International Patent Application WO 98/01447 discloses compounds of formula (Tic) : : :
Su Rr? i . i, {Hn ey y . (Ie)
R* rR? wherein R! represents -NHC(=0)R® wherein R® represents (C;-Cy)alkyl; R? and R? represent hydrogen or fluoro; R? and R’ are independently hydrogen or methyl; R® represent pyridyl, optionally substituted by substituents selected from (C 1-Cyalkyl (optionally substituted), halo, trifluoromethyl, (Ci-Ca)alkyl-S(O),- (wherein nis 0, 1 or 2), (Ci-Cyalkyl SOjamino, (C;-Cs)alkanoylamino, carboxy, hydroxy, amino, (Ci-
Ca4)alkylamino, di~(C;-Cy)alkylamino, (Cy-Cy)alkoxycarbonyl, carbamoyl, N-(C;-
Cs)alkylcarbamoyl, di-(N-(C}-Cu)alkyl)carbamoy] (wherein the (C,;-C,)alkyl group on groups in the last two mentioned carbamoyl groups is optionally substituted by hydroxy, (C;-Ce)alkoxy or (C;-Cs)alkoxycarbonyl), (C-Cy)alkenyl (optionally substituted by carboxy or (C;-Cg)alkoxycarbonyl), (Ci-Ca)alkoxy, cyano, or nitro . groups. :
An example of this class of compounds is shown in formula (IId) 0)
OOD, me - TER on
(iii) International Patent Application No. WO 95/07271 discloses compounds of formula (Ile)
Ne R2 hil i in HN Gn {x (Ile)
Oo wherein X represents O, S, SO, SO;, SNR! or SONR'": R represents hydrogen, (C;- 5 Cpg)alkyl optionally substituted with one or more of the following : F, Cl, hydroxy, (C;-
Cg)alkoxy, (C;-Cg)acyloxy or -OCH,Ph or R represents (Cs-Ce)cycloalkyl, amino, (C;-
Cg)alkylamino, (C,-Cs)dialkylamino or (C;-Cg)alkoxy; R' represents hydrogen except when X is O, then R! can be hydrogen, CH3, cyano, -CO,H, CO;R or (CH)mR" (mis 1 or 2); R? represents independently hydrogen, F or CI; R? represents hydrogen or CHs;
R'" independently represents hydrogen, (C1-Ca)alkyl (optionally substituted with chloro, fluoro, hydroxy, (C;-Cg)alkoxy, amino, (C;-Csg)alkylamino, or (C;-Cs)dialkylamino) or p-toluenesulfonyl; R! represents hydrogen, hydroxy, OR, OCOR, NH,, NHCOR or
NR); andnis 0,1 or 2. :
An example of this class of compounds is shown in formula (IIf)
I
LO Ru (116)
F Nay Ce 0 (iv) International Patent Application WO 95/25106 discloses compounds of formula (Ig) . Rd R! X Ji 5 N N O
J) : ENG ({g)
Ee) ) where R is hydrogen atom, (C;-Cs)alkyl, (C;-C¢)cycloalkyl, amino, (C1-Cy)alkylamino, . 20 (C,-Cg)dialkylamino, (C;-Cs)alkoxy or (C;-Cg)halogen alkyl; R! and R® are each and independently =~ represents hydrogen atom, halogen atom, (Ci-Cylalkyl, (C;-
Ce)cycloalkyl, ~(CH2)m-OR!! or ~C(=0)-R"; X and Y are each and independently represents hydrogen atom, halogen atom; R* and R® are each and independently represents hydrogen atom, (C;-Cs)alkyl, (Ci-Cs)alkoxy, (Ci-Cg)alkylthio, -(CH,),,-OR® l . -O-(CH2)m-OR’!, NR*”R%, -N=CH-NR*R®, -C(=0)-NR*’R*? or —~(CHy)i-C(=A)-R* or they may combine together to form =0, =NR*, =S, =CR*R** or an optionally substituted, unsaturated or saturated 5 or 6 membered hetero ring having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; R'' and R' are each and independently represents hydrogen atom, (Ci-
Cglalkyl or methoxymethyl; R*! is hydrogen atom, -(CH,)m-OH, (C1-Ca)alkyl, (Ci-
Cs)alkoxy, -O-CHz-O-C(=0)-R'' or (CH,)-C(=0)-OR'’; R* and R% are each and independently represents hydrogen atom, -(CH;),,-OR'}, (Ci-Cg)alkyl, -C(=0)-R*' -
C(=0)-NR''R"?, -(CH,),-phenyl, thiazol-2-yl or they may combine together to form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group or a thiomorpholino group, each of which may be substituted ‘by (C;-Cg)alkyl or -(CHy)p-
OH; R® is hydrogen atom, -OR’', (C,-Cglalkyl, (C;-Cs)alkoxy, -(CHy),-phenyl,
NR*R*, -NH-C(=NH)-NH,, [1,2,4]triazol-4-yl or cyano; R* and R> are each and independently represents hydrogen atom, (C;-Cg)alkyl, -C(=0)-R*! or —(CHa)p-phenyl;
Ris hydrogen atom, (C;-Csg)alkyl substituted by one or more hydroxy; (C2-Cg)alkenyl, (C-Cg)halogenalkyl, (CHz)m-OR'", -(CH)m-C(=0)-R*', —C(=0)-(CH,).-OR* or tosyl;
A is oxygen atom or ethyleneketal; --- is a double bond or a simple bond; m’s are each and independently 0, 1 or 2; nis 0 or 1; p’s are each and independently 1, 2, 3 or 4;
An example of this class of compounds is shown in formula (ITh)
E 0 e-mn— d Hoa (11h) — Hccn, ¢] (v) Intemational Patent Application WO 96/13502 discloses compounds of formula (I)
. rR? 1 ot Hy 0 am
R* EI
Oo
Q is selected from the structures (a), ®), (c), (d) and (e); (CH2n, 6R R3 RIE 3R R3 2R_3R (CH2)n i AN RT TN 02R” TN 3R 2R TAN (a) -(b) (c) (d) (e)
R'is H or F, OR’, SR”, NR*R®, CN, (C;-C4)alkoxycarbonyl, carboxamide, (Ci-Cs)acyl optionally substituted with one or more of the following : fluorine, hydroxy, (C;-
Cqalkoxy, (Cy-Cs)acyloxy; NHO(C;-Cs)alkyl or NHOCH;Ph, NSO,R where R is (Ci-
Ce)alky! optionally substituted with one or more F, Cl, (C;-Cg)alkoxy or phenyl; R® is independently selected from hydrogen or fluorine, hydroxy, OR where R is (C;-Cg)alkyl; (C1-Cy)alkyl or Ph; R’ is independently selected from H, phenyl, pyridyl or (C,-Cs)alkyl which can be optionally substituted with F, Cl, hydroxy, (C,-C3)alkoxycarbonyl, (C;-
Cs)acyloxy, (C1-Cs)alkoxy or N(C;-Cy alkyl); R? is independently H, OCH;, F or CL; R®. is hydrogen, (C;-Cg)alkyl optionally substituted with one or more of the following : F,
Cl, hydroxy, (Ci-Cg)alkoxy, (C;-Cs)acyloxy; (C3-Cs)eycloalkyl, amino, (C;-
Cs)alkylamino, (C,-Cs)dialkylamino, (Ci-Cs)alkoxy; Ris 0, S, NR, CR''R", (OR), where R is (C-Cg)alkyl; O(CHz)m O, (SR); where R is (C;-Cg)alkyl; S(CH;)mS; R is H, (C1-Cg)alkyl optionally substituted with one or more of the following : F, Cl, -CN, OH, (Ci-Cg)alkoxy, (C;-Cs)acyloxy, (C,-Cg)alkoxycarbonyl, phenyl; (C;-Cg)acyl optionally substituted with one or more of the following : hydroxy, (C,-Cs)alkoxy, (C,-Cg)acyloxy; (Cy-Cg)alkoxycarbonyl, carboxamide optionally substituted with a (C;-Cs)alkyl or phenyl on the carboxamide nitrogen; phenyl, optionally substituted with one or more of the following : halogen, CN, (C;-Cs)alkoxy, (Ci-Cs)alkoxycarbonyl, (C)-Cj)alkyl ; optionally substituted with one or more of F or (C;-Cs;) alkoxy; R® and R® are independently selected from H, (C;-Cg)alky! optionally substituted with one or more of the following : F, Cl, -CN, OH, (C;-Cs)alkoxy, (C-Cg)acyloxy, (C;-Cs)alkoxycarbonyl, phenyl; (C;-Cg)acyl optionally substituted with one or more of the following : hydroxy, ’ (Cy-Cg)alkoxy, (C,-Cg)acyloxy, amino, (Ci-Cpacylamino, amino (C;-C,)acylamino; , benzoyl optionally substituted with one or more of the following F, Cl, hydroxy, (C;-
Cg)alkoxy, (C1-Ca)acyloxy, amino, (C;-Cyacylamino, (C,-C,) alkoxycarbonylamino; (C,-Cg)alkoxycarbonyl, benzyloxycarbonyl, tertbutoxycarbonyl; carboxamide optionally substituted with a (Cy-Cy)alkyl or phenyl on the carboxamide nitrogen; trifluoracetyl,
CO(C;-Cs alkyl); R'is H, OR’, NHR’, (C,-Cg)alkyl optionally substituted with phenyl;
R'" and R" are independently selected from H, F, (C;-Cy)alkyl optionally substituted with halogen, hydroxy, (C-Caalkoxy, (Ci-Cy)alkoxycarbonyl, phenyl; (C1-Cp)acyl, (Ci-
Cy)alkoxycarbonyl, CN; R'7 is O or S; R'® and R"® are independently selected from H, (Ci-Cs)alkyl optionally substituted with halogen, hydroxy, (C;-Cs)alkoxy; OH, (C;-
Cy)alkoxy optionally substituted with hydroxy or (C;-Ca)alkoxy; NR®R®, -0OC(0) (Cy- Cyalkyl; R¥ is H, CH;;nisOor1; mis 2 or 3;
An example of this class of compounds is shown in formula (I1j) fo) wd ex 0 (1x) =~ — Feccn, . 10) (vi) International Patent Application WO 97/27188 discloses compounds of formula (IL k) :
SN R2 H : 5_
R {OO og | K)
R* . RS R
R! is of the formula -NHC(=0)(C,-C4)alkyl, -NHS(0)a(C,-Cs)alkyl, wherein n is 0,1o0r 2 or R! is hydroxy; R? and R? are independently hydrogen or fluoro; R? is hydrogen, . methyl, ethyl or oxo; R’ is hydrogen, (C;-Cg)alkyl, (C;-Ce)alkenyl, (C2-Cs)alkymyl, or of the formula R%(CH2)m wherein m is 1-4 and R® is trifluoromethyl, difluoromethyl, )
fluoromethyl, (Ci-Ca)alkoxy, (Ci-C4)alkyl,S(O), wherein p is 0, 1 or 2, (C;-
Ce)alkanoyloxy, di-(N-(C;-Cy)alkyl)amino, N-((C; -Ca)alkyl)(C 1-Cq)alkanoylamino, ) cyano, carboxy, (C;-Cs)alkoxycarbonyl, carbamoyl, -di-(N-(C;-Cq)alkyl)carbamoyl, N- ((Cy-Cy)alkyl)(C;-Cy)alkanesulphonamido, N'-((C-Cyalkyl)-di-(N> -(Cy-Cs)alkyl)ureido or of the formula ~OC(=O)NRR®) or N(R’)SO,NR’(R®) wherein R’ and R® are independently hydrogen or (C,-Cy)alkyl and R’ is (C)-Cy)alkyl; or m is 2-4 and R°® is hydroxy, (C-Cys)alkanoylamino, amino, (C-Cylalkylamino, (Cs-
Ca)alkanesulphonamido, ureido, di-(N>-(C;-Cy)alkylureido or of the formula
NHSO,NR'(R®);
An example of this compound is shown in fig (111) ’ 3 FR 1 nf od Ho Cr i am)
HAc (vii) International Patent Application WO 98/01446 discloses compounds of formula (Im)
RS R? o oN 3d * (Iim)
Dad R3 “rt
R'is of the formula -NHC(=0)R® wherein R® is (C;-Coalkyl; R? and R® are independently hydrogen or fluoro; R* and R® are independently hydrogen or methyl; R® is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms and optionally substituted by substituents selected from (C;-Cy)alkyl (optionally substituted), halo, trifluoromethyl, (C1-Ca)alkylS(O)n. (whereinnis 0,1 or 2), (Ci-CyalkylS(O), amino, (C;-Cy)alkanoylamino, carboxy, hydroxy, amino, (C;-
Ca)alkylamino, di(C;-Cs)alkylamino, (Cy-Cylalkoxycarbonyl, carbamoyl, N-(C,-
Ca)alkylcarbamoyl, -di-(N-(C,-Cs)alkyl)carbamoyl, [wherein (C,-Cs)alkyl group or ‘ groups in the last two mentioned carbamoyl substituents is optionally substituted by hydroxy, (Ci-Caalkoxy or (Ci-C)alkoxycarbonyl], (Cy-Ca)alkenyl (optionally ) 25 substituted by carboxy or (C;-Cs)alkoxycarbonyl), (C;-Cq4)alkoxy, cyano or nitro;
An example of this compound is shown in fig (IIn) \ R? 0
CHOC, am)
N . 4
With an objective to develop novel compounds effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as
MRSA, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp, Clostridia spp. -species and acid-fast organisms such .as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp., we focussed our research to develop new compounds effective against the above mentioned organisms. Efforts in this direction have led to the preparation of compounds having general formula (I) as defined above.
The present invention provides novel Oxazolidinones of the general formula (I) as defined above and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
A process for the preparation of novel oxazolidinones of the formula (I) as defined above and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates is also described.
An aspect of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their analogs, their demnvatives, their , tautomers, their stereoisomers, their polymorphs, their salts, solvates or their mixtures in
ES combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Novel intermediates of formulae , (VI), VII), (X), , (XVI) (XVIII), and a process for their preparation and their use in the preparation of compounds of formula (I) is also provided.
The present invention relates to compounds having the general formula (I), ’ 2 ol x 2nd Hn o ® vie + —(_ rt where R! represents halo, azido, thioalcohol, isothiocyanate, OR, NHR* or NR%),, where R* represents hydrogen atom, or substituted or unsubstituted groups selected from acyl, thioacyl, (C;-Cs)alkoxycarbonyl, cyclo(C;-Cs)alkoxythiocarbonyl, (C,-
Ce)alkenyloxycarbonyl, (Cy-Ce)alkenylcarbonyl, aryloxycarbonyl, (Ch-
Cs)alkoxythiocarbonyl, (C2-Cé)alkenyloxythiocarbonyl, aryloxythiocarbonyl, -C(=0)-
C=O) (Ci-Celalkyl, -C(=0)-C(=0)-aryl, -C(=0)-C(=0)- (C;-Ce)alkoxy, -C(=0)-
C(=0)-aryloxy, -(C=S)-S-(C;-Cg)alkyl, -(C=S)-NH;,, -(C=S)-NH-(C;-Ce)alkyl, -C(=S)-
N-((C1-Co)alkyl);, -C(=S)-NH-(C,-C¢)alkenyl, (C=S)-(C=0)-(C;-Cé)alkoxy, -(C=S)- (C=0)-aryloxy, -C(=5)-O-(C=0)- (C;-Cs)alkyl, C(=S)-C(=S)- (C-Cs)alkyl, -C(=S)-
C(=S)-aryl, thiomorpholinylthiocarbonyl or pyrrolidinylthiocarbonyl; R? and R® may be same or different and independently represent hydrogen, halogen atom, (C;-Cs)alkyl group, halo(C;-Cq)alkyl, cyano, nitro, SR?, NR? OR® where R? represents substituted or unsubstituted (C;-Ce)alkyl group, or halo(C;-Ce)alkyl; Z represents S, O, =CH or NR? where RP represents hydrogen or substituted or unsubstituted (Ci-Ce)alkyl, (C,-
Cealkenyl, (Ci-Ce)cycloalkyl, (Ci-Ce)alkoxy, aryl, aralkyl, aryloxy, (C;- , 25 Cgalkylcarbonyl, arylcarbonyl, (C1-Ce)alkoxycarbonyl “or aryloxycarbonyl; Y! represents =O or =S group. and Y? and Y? independently represent hydrogen, halogen, : cyano, nitro, formyl, hydroxy, amino, =O, =S group or substituted or unsubstituted groups selected from (C1-Co)alkyl, hydroxy(Cy-Ce)alkyl, (Ci-Cs)alkoxy(C;-Cg)alkyl, (Cy-Ce)alkoxycarbonyl, carboxy(C, _Co)alkyl, (C1-Ce)alkylsulfonyl, (Ci- ]
Ce)alkylcarbonylamino(C;-Ce)alkyl, arylcarbonylamino(C;-Ce)alkyl, (C-
Ce)alkylcarbonyloxy(Ci-Ce)alkyl, amino(C,-Cgalkyl, mono(C,-Cg)alkylamino, di(C;- yo
Ce)alkylamino, arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y* when present on adjacent carbon atoms together may also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates.
Suitable groups.represented by R* may be selected from hydrogen atom, (C,-
C7)acyl group such as ~C(=O)H, —C(=0)CH;, -C(=0)CH,CH3;, -C(=0)(CH,),CH;, -
C(=0)(CHz2);CH3, -C(=0)(CH2)«CH3, ~C(=0)(CH;)sCHs, -C(=O)Ph and the like, the acyl group may be substituted; thio(C,~C;)acyl group such as —~C(=S)H, —C(=S)CHs, -
C(=S)CH,CH3;, -C(=S)Ph and the like, the thioacyl group may be substituted; (C,-
Ce)alkoxycarbonyl group containing (C;-Ce)alkyl group which may be linear or branched such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and the like, the (C;-Ce)alkoxycarbonyl group may be substituted; cyclo(Cs-Co)alkoxythiocarbonyl group such as cyclopropoxythiocarbonyl, cyclobutoxythiocarbonyl and the like, the cyclo(C;-Ce)alkoxythiocarbonyl may be substituted; (C,-Cg)alkenylcarbonyl such as ethenylcarbonyl, propenylcarbonyl, butenylcarbonyl and the like, the (C-Co)alkenylcarbonyl may be substituted; (C,-
Ce)alkenyloxycarbonyl. group such as ethenyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl and the like, the (C,-Cg)alkenyloxycarbony! may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, benzyloxycarbonyl group and the like, ihe aryloxycarbonyl group may be substituted; (Ci Cg)alkoxythiocarbonyl grown euch as .
CH;0-C(=S)-, CoH;0-C(=S)- C3;H;0-C(=S)- and the like, which may be substituted; . (Cy-Cg)alkenyloxythiocarbonyl group such as ethenyloxythiocarbonyl, :
propenyloxythiocarbonyl, butenyloxythiocarbonyl and the like, the (C,-
Ce)alkenyloxythiocarbonyl group may be substituted; aryloxythiocarbonyl group such as phenylO-C(=S)-, benzylO-C(=S)- and the like, which may be substituted; -C(=0)-
C(=0)-(C1-Ce)alkyl group such as -C(=0)-C(=0)methyl , -C(=0)-C(=O)ethyl, -C(=O0)-. C(=O)propyl and the like, which may be substituted; -C(=0)-C(=0)-ary] group such as -
C(=0)-C(=O)phenyl, -C(=0)-C(=O)naphthyl and the like, which may be substituted; -
C(=0)-C(=0)-(C|-C¢)alkoxy group such as. -C(=0)-C(=O)methoxy, -C(=0)-
C(=0)ethoxy, -C(=0)-C(=O)propyloxy and the like, which may be substituted; -C(=0)-
C(=0)-aryloxy group such as -C(=0)-C(=O)phenyloxy, -C(=0)-C(=O)benzyloxy, which may be substituted; -(C=S)-S~(C,-Ce)alkyl such as -(C=S)-S-methyl, -(C=S)-S- ethyl, -(C=S)-S-propyl and the like, which may be substituted; -(C=S)-NH,; -(C=S)-NH- (C1-Ce)alkyl such as -(C=S)-NH-methyl, -(C=S)-NH-ethyl, -(C=S)-NH-propyl and the like, which may be substituted; -C(=5)-N~((C;-Cg)alkyl), such as -C(=S)-N-(methyl),, -
C(=5)-N-(ethyl), -C(=S)-N-(propyl), and the like, which may be substituted; -C(=S)-
NH-(C;-Ce)alkenyl such as -C(=S)-NH-ethenyl, -C(=S)-NH-propenyl, -C(=S)-NH- butenyl and the like, which may be substituted; -(C=S)-(C=0)-(C,-Ce)alkoxy such as - (C=S)-(C=0)-methoxy, -(C=S)-(C=0)-ethoxy, -(C=S)-(C=0O)-propoxy and the like, which may be substituted; -(C=S)-(C=0)-aryloxy such as -(C=S5)-(C=0)-phenyloxy, - (C=S)-(C=0)-naphthyloxy and the like, which may be substituted; -C(=S)-0-(C=0)- - (Cy-Ce)alkyl such as -C(=S)-O-(C=0)-methyl, -C(=S)-O-(C=0)-ethyl, -C(=S)-0-(C=0)- propyl and the like, which may be substituted; -C(=S)-C(=S)~(C;-Cs)alkyl group such as -C(=S)-C(=S)methyl, -C(=S)-C(=S)ethyl, 2C(=8)-C(=S)propy! and the like, which may be substituted; -C(=S)-C(=S)aryl group such as =-C(=S)-C(=S)phenyl, -C(=S)-
C(=S)naphthyl and the like, which may be substituted; thiomorpholinylthiocarbonyl or pyrrolidinylthiocarbonyl. © When the groups represented by R* are substituted, the substituents may be selected from halogen atom such as chlorine, fluorine, bromine and iodine; hydroxy, amino, mono(C;-Ce)alkylamino such as methylamino, ethylamino, propylamino and the ) like, di(C;-Ce)alkylamino such as dimethylamino, diethylamino, methylethylamino,
dipropylamino, ethylpropylamino and the like, cyano, nitro, alkoxy, aryl, hydroxyaryl, pyridyl, hydroxyalkyl, alkoxyaryl or carboxyl and its derivatives. ) } " Suitable groups. represented by R? and R? may be selected from hydrogen, halogen atom such as fluorine, chlorine or bromine; (C1-Co)alkyl group such as methyl, , ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, n-hexyl and the like; halo(Ci-Cs)alkyl group such as halomethyl, haloethyl, halopropyl, trihalomethyl and the like, wherein the halo group is selected from fluorine, chlorine, bromine or iodine; cyano, nitro; SR®, NR®, OR? where R? represents substituted or unsubstituted (C;-Cs)alkyl group such as methyl, ethyl, propyl, isopropyl and the like; halo(C;-Cy)alkyl such as halomethyl, haloethyl, halopropyl, haloisopropyl and the like, where the halo group is selected from fluro, chloro, bromo or iodo.
The substituents on R* are selected from hydroxy, halogen, nitro, amino, alkoxy, carboxyl or cyano : :
Suitable groups represented by Z may be selected from S, O, =CH or NR? where
R° represents hydrogen or substituted or unsubstituted (C1-Cg)alkyl such as methyl, ethyl, propyl and the like, which may be substituted; (C2-Ce)alkenyl such as ethenyl, propenyl, butenyl and the like, which may be substituted; (Ci-Ce)cycloalkyl such as cyclopropyl, cyclobutyl and the like, which may be substituted; (Ci-Ce)alkoxy such as methoxy, propoxy, isopropoxy and the like, which may be substituted; aryl group such - as phenyl, naphthyl and the like, which may be substituted; aralkyl such as benzyl, phenethyl and the like, which may be substituted; aryloxy such as phenyloxy, naphthyloxy and the like, which may be substituted; (C;-Ce)alkylcarbonyl such as methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like, which may be substituted; * arylcarbonyl such as phenylcarbonyl, naphthylcarbonyl and the like, which may be substituted; (C;-Ce)alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like, which may be substituted; or aryloxycarbonyl such as phenyioxycarbonyi, naphinyioxycarbonyi and ihe like, which may be substituted,
The substituents on R® are selected from hydroxy, halogen, pyrrolidinylthiocarbonyl, nitro, amino, alkoxy, carboxyl or cyano. .
Y! represents =O or =S group, Y? and Y’ are selected from hydrogen, halogen such as fluorine, chlorine, bromine or iodine; cyano, nitro, formyl, hydroxy, amino, =O, =S group, substituted or unsubstituted (C,-C¢alkyl such as methyl, ethyl, n-propyl, . isopropyl, n-butyl, iso-butyl, t-butyl and the like; hydroxy(C;-Ce)alkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl and the like, which may be substituted; (Ci-Ce)alkoxy(C,-Ce)alkyl group such as methoxymethyl, methoxyethyl, ethoxyethyl, ethoxymethyl, methoxypropyl, propoxymethyl, propoxyethy! and the like, which may be substituted; (C,-Cg)alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and © the like, which may be substituted; carboxy(C,-Ce)alkyl such as CH3;-COOH, CH;-CH,-
COOH and the like, which may be substituted; (C,-Cs)alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and the like, which may be substituted; (C;-
Cs)alkylcarbonylamino(C,-Ce)alkyl groups such as methylcarbonylaminomethyl, ethylcarbonylaminomethyl, methylcarbonylaminoethyl, ethylcarbonylaminoethyl and : the like, which may be substituted; arylcarbonylamino(C,-C¢)alkyl such as phenylcarbonylaminomethyl, phenylcarbonylaminoethyl, naphtylcarbonylaminomethyl, naphthylcarbonylaminoethyl and the like, which may be substituted; (C;-
Cé)alkylcarbonyloxy(Ci-Cs)alkyl ~~ group such 25 methylcarbonyloxymiethyl, ethylcarbonylxoymethyl, methylcarbonyloxyethyl, propylcarbonyloxymethyl, propylcarbonyloxyethyl, propylcarbonyloxypropyl and the like, which may be substituted; amino(C;-C¢)alkyl such as aminomethyl, aminoethyl, aminopropyl! and the like, -which may be substituted; “mono(C;-Cg)alkylamino such as methylamino, ethylamino, propylamino and the like, which may be substituted; di(C;-Cg)alkylamino sich. as dimethylamino, diethylamino, methylethylamino, dipropylamino, ethylpropylamino and the like, which may be substituted; arylamino such as phenylamino, benzylamino and the like, which may be substituted; (C;-Cs)alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, which may be substituted; aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted: ] aralkyl such as benzyl, phenethyl, CsHsCH,CH,CH,, naphthylmethyl and the like, the aralkyl group may be substituted; heteroaryl groups such as pyridyl, thienyl, furyl, ~ pymolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, which may be substituted; heteroaralkyl such as imidazolemethyl, imidazoleethyl, pyridylmethyl, furyl methyl, oxazolemethyl, , imidazolyl and the like, which may be substituted; heterocyclyl group such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like; heterocycloalkyl groups such as pyrrolidinemethyl, piperidinemethyl, morpholinemethyl, piperazinemethyl and the like, which may be substituted.
When the groups represented by Y* and Y? are substituted, the substituents may be selected from hydroxy, nitro, cyano, amino, (ters--butyldimethylsilyloxy) TBSO, halogen atom, (C;-Cg¢)alkyl, (Ci-Ce)alkoxy, (Cs-Ce)cycloalkyl, aryl group such as phenyl, naphthyl and the like, benzyloxy, acyl group such as formyl, acetyl, and the like, - carboxyl or acyloxy group such as formyloxy, acetyloxy and the like.. | :
Suitable cyclic structure formed by YZ and Y? when present on adjacent carbon atoms which they-are attached may be selected from substituted or unsubstituted benzene, pyridine, pyrrolidine, furan, thiophene, morpholine, piperazine, pyrrole and the like. ” ~~ Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N’-diacetylethylenediamine, betaine,. caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ‘N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N’- diphenylethylenediamine, N,N’-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclchexylamine, ssiforain, benzylamine, phenylethylamine, dialkyiamine, iriaikyiamine, thiamine, amincpyrimidine aminopyridine, purine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, .
alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; ] guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl such as methyl, ethyl, propyl and the like; alkenyl such as ethenyl, propenyl, butenyl and the like; alkynyl such as ethynyl, propynyl and the like; ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compounds according to this invention include: (5R)-3-[3-fluoro-4-(2-ox0-1,3-oxazolan-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolan-2- one or its salts; (5R)-3-[3-fluoro-4-(2-thioxo-1,3-0xazolan-3-yl)phenyl]-5-hydroxymethyl-1 ,3-0xazolan- 2-one or its salts; (5R)-3-[3-fluoro-4-(2-thioxo-1 ,3-thiazolan-3-yl)phenyl]-5-hydroxymethyl- 1,3-oxazolan- 2-one or its salts; (5R)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl}-5-hydroxymethyl-1,3- oxazolan-2-one or its salts; 3- {2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1 ,3-oxazolan-3-yl]phenyl}-2,3- dihydrobenzo [d][1,3]Joxazol-2-one or its salts; 3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolan-3-yl]phenyl}-6-methyl-2,3- dihydrobenzo[d][1,3]Joxazol-2-one or its salts; 3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-0xazolan-3-yl]phenyl} -5-methyl-2,3- dihydrobenzo[d][1,3]oxazol-2-one or its salts; (5R)-5-hydroxymethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl]-1,3-
X oxazolan-2-one or its salts;
(SR)-3-[2-fluoro-4-(2-0x0-1,3-oxazolan-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolan.2. one or its salts; } (SR)-3-{3,5-fluoro-4-(2-0xo-1,3-0xazolan-3-yDphenyl]-5-hydroxymethyl-1 3-oxasolan. 2-one or its salts; : } (5R)-5-hydroxymethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl}-1,3-oxazolan-2-one or its salts; 3-{4-[(5R)-5-hydroxymethyl-2-oxo-1,3-oxazolan-3-yl]phenyl} -2,3- dihydrobenzo[d][1,3] oxazol-2-one or its salts; (5R)-3-[3-fluoro-4-(3-methyl-4-oxo- 1-imidazolidinyl)phenyl}-5-hydroxymethyl-1 ,3- oxazolan-2-one or its salts; : (5R)-3-{3-fluoro-4-[3-(4-methoxybenzyl)-4-oxo-1 -imidazolidinyl]phenyl}-5-
" hydroxymethyl-1,3-oxazolan-2-one or its salts; . (5R)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3- oxazolan-2-one or its salts; : )
(5R)-5-hydroxymethyl-3-[4-(3-methyl-2-ox0-1 -imidazolidinyl)phenyl]-1,3-oxazolan-2- one or its salts; oT (5R)-5-hydroxymethyl-3-[4-(3-benzyl-2-oxo- 1-imidazolidinyl)phenyl}-1,3-oxazolan-2- one or its salts; )
: (5R)-3-{3-fluoro-4-(2-oxo-3-phenyl-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-
oxazolan-2-one or its salts;
- (5R)-3- {3-fluoro-4-[3-(fluorophenyl)-2-oxo-1-imidazolidinyljphenyl}-5- hydroxymethyl-1,3-oxazolan-2-one or its salts; (5R)-azidomethyl-3-[3-fluoro-4-(2-oxo-1 ,3-0xazolan-3-yl)phenyl]}-1 ,3-oxazolan-2-one or its salts; :
(5R)-azidomethyl-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-one or its salts; oo 3-{4-{(5R) ¢ azidomethyl-2-oxe-1,3-oxazolan-3-y11-2-fluoronhenyl} -6-methyl-2, 3- dihydro benzo[d][1,3]oxazol-2-one or its salts;
3-{4-[(5R)-5-azidomethyl-2-0x0-1,3 -oxazolan-3-yl]-2-fluorophenyl}-5-methyl-2,3- dihydro benzo[d][1,3]oxazol-2-one or its salts; (SR)-5-azidomethyl-3-[4-(2-0x0-1 ,3-oxazolan-3-yl)-3-triflucromethylphenyl]-1,3- oxazolan-2-one or its salts; (5R)-5-azidomethyl-3-[2-fluoro-4-(2-0xo-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; - (5R)-azidomethyl-3-[3,5-difluoro-4-(2-oxo-1 3-oxazolan-3-yl)phenyl]- 1,3-oxazolan-2- one or its salts; } (5R)-5-azidomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; ~ 3-{4-[(5R)-5 -azidomethyl-2-oxo-1,3-0xazolan-3-yl]phenyl1}-2,3-dihydrobenzo[d][ 1 3] oxazol-2-one or its salts; (5R)-5-azidomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1 -imidazolidinyl)phenyl]-1,3- oxazolan-2-one or its salts;
(5R)-5-azidomethyl-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-1,3- : oxazolan-2-one or its salts; (5R)-5-azidomethyl-3- {3-fluoro-4-[3-(4-fluorophenyl)-2-oxo-1-imidazolidinyljpheny1} - 1,3-oxazolan-2-one or its salts; (5R)-aminomethyl-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts;
: (5R)-aminomethyl-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-ome or its salts; (5R)-5-aminomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl]-1,3- oxazolan-2-one or its salts;
(5R)-5-aminomethyl-3-[4-(2-0xo-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; (5R)-5-aminomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-1,3-
’ ‘0xazolan-2-one or its salts;
Claims (58)
1. A compound of the formula (I) ; Y2 ja 1 20nd Hn" 0) YI + —{_& wherein R' represents halo, azido, isothiocyanate, thioalcohol, OR*, NHR* or NERY, where R* represents hydrogen atom, or substituted or unsubstituted groups selected from acyl, thioacyl, (C;-Cs)alkoxycarbonyl, (C;-Ce)cycloalkoxythiocarbonyl, (Cz- Ce)alkenyloxycarbonyl, (C,-C¢)alkenylcarbonyl, aryloxycarbonyl, (Ci- Ce)alkoxythiocarbonyl, (C»-Cs)alkenyloxythiocarbonyl, aryloxythiocarbonyl, -C(=0)- C(=0)-alkyl, -C(=0)-C(=O)-aryl, -C(=0)-C(=O)-alkoxy, -C(=0)-C(=0)-aryloxy, - (C=S)-S-alkyl, -(C=S)-NH,, -(C=S)-NH-alkyl, -C(=S)-N-(alkyl);, -C(=S)-NH-alkenyl, (C=8)-(C=0)-alkoxy, -(C=S)-(C=0)-aryloxy, -C(=S)-0-(C=0)-alkyl, C(=S)-C(=S)- alkyl, -C(=S)-C(=S)-aryl, thiomorpholinylthiocarbonyl or pyrrolidinylthiocarbonyl; R? and R® are same or different and independently represent hydrogen, halogen atom, (C;- Ce)alkyl group, halo(Ci-Ce)atkyl, cyano, nitro, SR?, NR? OR? where R* represents substituted or unsubstituted (C,-Cg)alkyl group, or halo(C-Cs)alkyl; Z represents S, O, =CH or NR? where R® represents hydrogen, or substituted or unsubstituted (Cy-Ce)alkyl, (C2-Cg)alkenyl, (Ci-Co)eycloalkyl, (C1-C)alkoxy, aryl, aralkyl, aryloxy, (Ci- Cg)alkylcarbonyl, arylcarbonyl, (Ci-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y? and'Y® independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (Ci-Ce)alkyl, hydroxy(C;-Ce)alkyl, (C-Cg)alkoxy(C-Ce)alkyl, (Ci-Coalkoxycarbonyl, * carboxy(Ci-Coalkyl, (Cr-Coalkylsulfonyl, ~~ (Ci- Cg)alkylcarbonylamino(C,-Ce)alkyl, arylcarbonylamino(C,;-Ce)alkyl, (Cy- Ce)alkylcarbonyloxy(Ci-Cealkyl, amino(C;-Cg)alkyl, mono(C;-Ce)alkylamino, di(C;- Cealkylamino, arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaratkyl, heterocyclyl or heterocycloalkyl, Y2 and Y® when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered ]
aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates.
2. The compound according to claim 1, wherein the substituents on R* are selected from halogen, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, alkoxy, aryl, hydroxyaryl, pyridyl, hydroxyalkyl, alkoxyaryl or carboxyl and its derivatives.
3. The compound according to claim 1, wherein the substituents on R® are selected from hydroxy, halogen, pyrrolidinylthiocarbonyl, nitro, amino, alkoxy, carboxy or cyano, :
4, The compound according to claim 1, wherein the substituents on Y* and Y* are selected from hydroxy, nitro, cyano, amino, terz-butyldimethylsilyloxy(TBSO), halogen, (Ci-Co)alkyl, (Ci-Ceo)alkoxy, (C3-Cs)cycloalkyl, aryl, benzyloxy, acyl, carboxyl or acyloxy groups.
5. The compound according to claim 1, wherein the cyclic structure formed by Y? and Y? is selected from substituted or unsubstituted benzene, pyridine, pyrrolidine, furan, thiophene, morpholine, piperazine or pyrrole.
6. A compound of the formula (I) as defined according to claim 1 which is selected from: (5R)-3-[3-fluoro-4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolan-2- "one or its salts; : (5R)-3-[3-fluoro-4-(2-thioxo-1,3-oxazolan-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolan- 2-one or its salts; (5R)-3-[3-fluoro-4-(2-thioxo-1,3-thiazolan-3-yl)phenyl]-5-hydroxymethyi-1 ,3-oxazolan- 2-one or its salts; (5R)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3- oxazolan-2-one or its salts; 3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-0xo0-1,3-0xazolan-3-yl}phenyl}-2,3- . dihydrobenzo [d][1,3]oxazol-2-one or its salts;
3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-oxo-1,3-0xazolan-3-yl]phenyl} -6-methyl-2,3- dihydrobenzo[d][1,3]oxazol-2-one or its salts; = 3-{2-fluoro-4-[(5R)-5-hydroxymethyl-2-o0x0-1 ,3-oxazolan-3-yl]phenyl}-5-methyi-2,3- dihydrobenzo{d][1,3]Joxazol-2-one or its salts;
(5R)-5-hydroxymethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl]-1,3- oxazolan-2-one or its salts; (5R)-3-[2-fluoro-4-(2-0x0- 1,3-oxazolan-3-yl)phenyl]-5-hydroxymethyl-1,3-oxazolan-2- one or its salts; (5R)-3-[3,5-tluoro-4-(2-0x0-1,3 -oxazolan-3-yl)phenyl]-5 -hydroxymethyl-1,3-oxazolan-
2-one or its salts; : (5R)-5-hydroxymethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl}-1,3-oxazolan-2-one or its salts; : : 3-{4-[(5SR)-5-hydroxymethyl-2-0x0-1,3-0xazolan-3-yl]phenyl} 23 -dihydrobenzo[d]
[1,3] oxazol-2-one or its salts;
(5R)-3-[3-fluoro-4-(3-methyl-4-o0xo0-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3- oxazolan-2-one or its salts; (5R)-3-{3-fluoro-4-[3-(4-methoxybenzyl)-4-oxo-1-imidazolidinyl]phenyl} -5- hydroxymethyl-1,3-oxazolan-2-one or its salts; (5R)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3-
oxazolan-2-one or its salts; (5R)-5-hydroxymethyl-3-[4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]-1,3-oxazolan-2- one or its salts; -
(5R)-5-hydroxymethyl-3 -[4-(3 “benzyl-2-oxo-1 -imidazolidinyl)phenyl}-1,3-oxazolan-2- one or its salts; :
(5R)-3-[3-fluoro-4-(2-ox0-3-phenyl-1-imidazolidinyl)phenyl]-5-hydroxymethyl-1,3- oxazolan-2-one or its salts; (5R)-3-{3-flucro-4-[2 (flucrophenyl)-2-oxo-1-imidazolidinyllphenyl}-5-hydroxymethyl
~~ -1,3-o0xazolan-2-one or its salts;
(5R)-azidomethyl-3-[3-fluoro-4-(2-ox0-1,3-o0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; :
’ (5R)-azidomethyl-3-[ 3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-one or its salts;
) 5 3-{4-[(5R)-5-azidomethyl-2-0x0-1,3-0xazolan-3-yl]-2-fluorophenyl}-6-methyl-2,3- dihydro benzo{d][1,3]oxazol-2-one or its salts; 3-{4-[(5R)-5-azidomethyl-2-ox0-1,3-0xazolan-3-yl]-2-fluorophenyl} -5-methyl-2,3- dihydro benzo[d][1,3]oxazol-2-one or its salts; (5R)-5-azidomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenylj-1,3-
oxazolan-2-one or its salts; : (5R)-5-azidomethyl-3-[2-fluoro-4-(2-ox0-1,3-0xazolan-3-yl)phenyl]-1 .3-oxazolan-2-one or its salts; (5R)-azidomethyl-3-[3,5-difluoro-4-(2-0x0-1,3-oxazolan-3-yl)phenyl}-1,3-oxazolan-2- - one or its salts;
(5R)-5-azidomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; 3-{4-[(5R)-5-azidomethyl-2-0x0-1,3-0xazolan-3-yl]phenyl}-2,3-dihydrobenzo[d][1,3] oxazol-2-one or its salts; (5R)-5-azidomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl}-1,3-
oxazolan-2-one or its salts; (5R)-5-azidomethyl-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-one.or its salts; (5R)-5-azidomethyl-3-{3-fluoro-4-[3-(4-fluorophenyl)-2-oxo-1-imidazolidinylJphenyl}- 1,3-oxazolan-2-one or its salts;
(5R)-aminomethyl-3-[3-fluoro-4-(2-oxo-1,3-0xazolan-3-yl)phenyl]-1,3-0xazolan-2-one or its salts; (5R)-aminomethyl-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-1,3-
oxazolan-2-one or its salts;
(5R)-5-aminomethyl-3-[4-(2-0x0-1,3-oxazolan-3-yl)-3-trifluoromethylphenyl]-1,3- oxazolan-2-one or its salts; :
] (5R)-5-aminomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts;
(5R)-5-aminomethyl-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-one or its salts; | . (5R)-5-aminomethyl-3-[3-fluoro-4-(3-benzyl-4-oxo-1-imidazolidinyl)phenyl]-1,3- oxazolan-2-one or its salts;
N-{(5S5)-3-{3-fluoro-4-(2-oxo0-1,3-0xazolan-3-yl)phenyl]-2-0xo0-1 3 -oxazolan-5-
ylmethyl} methanamide or its salts; N-{(5S)-3-[3,5-difluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl]-2-0xo0-1,3-oxazolan-5- ylmethyl} methanamide or its salts; )
N1-{(5S)-3-[3-fluoro-4-(2-ox0-1,3-0xazolan-3-yl)phenyl}-2-0xo0-1,3-oxazolan-5- ylmethyl} acetamide or its salts;
N1-{(5S)-3-[3-fluoro-4-(2-0x0-1,3-0xazolan-3-yl)phenyl}-2-oxo-1,3-oxazolan-5- ylmethyl} propanamide or its salts;
N1- {(5S)-3-[3-fluoro-4-(2-oxo- 1,3-oxazolan-3-yl)phenyl}-2-oxo0-1,3-oxazolan-5- ylmethyl} butanamide or its salts; N1-{(58)-3-[3-fluoro-4-(2-oxo-1,3-0xazolan-3-yl)phenyl}-2-0xo-1,3-oxazolan-5-
ylmethyl} pentanamide or its salts; N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl}-2-oxo-1,3-0xazolan-5- ylmethyl} heptanamide or its salts;
N1-{ (5S)-3-[3-fluoro-4-(2-oxo- 1,3-oxazolan-3-yl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} acrylamide or its salts; : N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl]-2-oxo-1,3-0xazolan-5- “ ylmethyl}-2,2,2-trifluoroacetamide or its salts;
© BthyK5S)-3-[2-flucro-4-(2 oxo-1,3-oxazolan-3-ylphenyll-2-0x0-1 3-0xazolan-5-
ylmethyl carbamoylmethanoate or its salts;
N1-{(5S)-3-[3-fluoro-4-(2-thioxo-1,3~oxazolan-3-yl)phenyl]}-2-oxo-1,3-oxazolan-5- ylmethyl} ‘acetamide or its salts;
N1-{(5S)-2-0x0-3-[4-(2-thioxo-1,3-0xazolan-3-yl)phenyl]-1,3-0xazolan-5-ylmethyl} acetamide or its salts;
N1-{(5S)-2-ox0-3-[3-fluoro-4-(2-thioxo-1,3-thiazolan-3-yl)phenyl}-1,3-oxazolan-5- ylmethyl} acetamide or its salts; N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1-imidazolidinyl)phenyl]-2-oxo-1,3- oxazolan-5-ylmethyl} acetamide or its salts; N1-{(5S)-3-[3-fluoro-4-(2-0x0-2,3-dihydrobenzo[d][ 1,3 ]Joxazol-3-yl)phenyl]-2-oxo0-1,3-
oxazolan-5-ylmethyl} acetamide or its salts; N1-{(5S)-3-[3-fluoro-4-(6-methyl-2-ox0-2,3-dihydrobenzo[d][1 ,3Joxazol-3-yl)phenyl]- 2-0x0-1,3-oxazolan-5-ylmethyl} acetamide or its salts; NI1- {(5S)-3-[3-fluoro-4-(5-methyl-2-0x0-2,3 -dihydrobenzo[d][1,3Joxazol-3-yl)phenyl]- 2-0x0-1,3-oxazolan-5-ylmethyl} acetamide or its salts;
N1-{(5S)-2-ox0-3-[4-(2-0x0-1 3-oxazolan-3-yl)-3-trifluoromethylphenyl]- 1,3-oxazolan- 5-ylmethyl} acetamide or its salts; N1-{(5S)-2-0x0-3-{4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl]-1,3-oxazolan- 5-ylmethyl}propanamide or its salts; N1-{(5S)-2-0x0-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-triflnoromethylphenyl]-1,3-oxazolan-
5-ylmethyl}heptanamide or its salts; N1-{(55)-2-0x0-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl}-1,3-oxazolan- 5-ylmethyl}acrylamide or its salts; - N1-{(5 S)-3-[2-fluoro-4-(2-0x0-1 ,3-oxazolan-3-yl)phenyl]-2-oxo-1 ,3-0xazolan-5- ylmethyl} acetamide or its salts;
N1-{(5S)-3-[3,5-difluoro-4-(2-oxo-1 3-oxazolan-3-yl)phenyl]-2-oxo-1 ,3-oxazolan-5- ylmethyl} acetamide or its salts; N1-{(5S)-3-[3,5-difluoro-4-(2-0x0-1,3-oxazolan-3-yl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} propanamide or its salts;
N1-{(58)-2-0x0-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-1,3-oxazolan-5-ylmethyl} acetamide or its salts; N1-{(5 S)-2-0x0-3-[4-(2-0x0-2,3-dihydrobenzo fai ,3Joxazol-3-yl)phenyl]- 1,3- oxazolan-5-ylmethyl} acetamide or its salts;
NI-{(5 S)-3-[3-fluoro-4-(3-methyl-4-oxo-1 -imidazolidinyl)phenyl]-2-oxo-1 ,3-oxazolan- 5-ylmethyl} acetamide or its salts; N1-{(58)-3-[3-fluoro-4-(3-benzyl-4-oxo-1 -imidazolidinyl)pheny1}-2-oxo-1 ,3-0xazolan-
5-ylmethyl} acetamide or its salts; N1-{(5 S)-3-[3-fluoro-4-(3-methyl-2-oxo-1 -imidazolidinyl)phenyl]-2-oxo0-1,3-0xazolan- 5-ylmethyl}acetamide or its salts; Ni1-{(5 S)-3-[4-(3 -methyl-2-oxo0-1 -imidazolidinyl)phenyl]-2-oxo-1,3-oxazolan-5- ylmethyl} acetamide or its salts; N1-{(55)-3-[4-(3-benzyl-2-0x0o-1 -imidazolidinyl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} acetamide or its salts; N1-{(58)-3-[3-fluoro-4-(3-phenyl-2-oxo- 1-imidazolidinyl)phenyl]-2-oxo-1,3-oxazolan- 5-ylmethyl} acetamide or its salts; N1-((5S)-3- {3-fluoro-4-[3-(4-fluorophenyl)-2-oxo-1 -imidazolidinyl]phenyl}-2-o0xo0-1,3- oxazolan-5-ylmethyl)acetamide or its salts; (5S)-3-[3-fluoro-4-(2-0x0-1,3-0xazolan-3 -yDphenyl]-5-(1 -thioxoethylaminomethyl)-1,3-
oxazolan-2-one or its salts; (58)-3-[3-fluoro-4-(2-0x0-1,3-oxazolan-3-yDphenyl]-5-(3,3,3-trifluoro-1-thioxopropy] aminomethyl)-1,3-oxazolan-2-one or its salts; .
(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1 -imidazolidinyl)phenyl]-5-(1-thioxoethylamino methyl)-1,3-oxazolan-2-one or its salts;
3-{2-fluoro-4-[(5S)-2-0x0-5-(1 -thioxoethylaminomethyl)-1 ,3-oxazolan-3-yl]phenyl}- 2,3-dihydrobenzo[d][1,3]Joxazol-2-one or its salts;
(5S)-3-[4-(2-0x0-1 ,3-oxazolan-3-yl)-3-trifluoromethylphenyl]-5-(1 -thioxoethylamino methyl)-1,3-oxazolan-2-one or its salts;
(58)-3-[3,5-difluoro-4-(2-oxo0-1,3-0xazolan-3-yl)phenyl]-5-( 1-thioxoethylamino methyl)-1,3-oxazolan-2-one or its salts;
(58)-3-[3,5-difluoro-4-(2-oxo0-1,3-0xazolan-3 ~-yDphenyl]-5-(1-thioxopropylamino - methyl)-1,3-0xazolan-2-one or its salts; (55)-3-[4-(2-0x0-1 ,3-oxazolan-3-yl)phenyl]-5-(1-thioxoethylaminomethyl)-1,3- oxazolan-2-one or its salts; (58)-3-[3-fluoro-4-(3-methyl-4-oxo-1 -imidazolidinyl)phenyl]-5-(1-thioxoethylamino + methyl)-1,3-o0xazolan-2-one or its salts; (58)-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl]-5-(1-thioxoethylamino methyl)-1,3-oxazolan-2-one or its salts; ~ NI- {(5S)-3-[3-fluoro-4-(2-oxo- 1,3-oxazolan-3-yl)phenyi]-2-oxo-1,3-oxazolan-5- ylmethyl} methylcarbamate or its salts; N1-{(5S)-2-0x0-3-[4-(2-0x0-1,3-0xazolan-3-yl)-3-trifluoromethylphenyl]-1,3-oxazolan- 5-ylmethyl} methylcarbamate or its salts;
N1-{(5S)-3-[3,5-difluoro-4-(2-0x0-1,3-oxazolan-3-yl)phenyl]-2-oxo-1,3-oxazolan-5- ylmethyl} methylcarbamate or its salts; N1-{(5S)-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl}-2-oxo-1,3-o0xazolan-5-ylmethyl} methyl carbamate or its salts;
N1-{(5S)-3-[3 ~fluoro-4-(3-methyl-4-oxo-1 -imidazolidinyl)phenyl]-2-oxo0-1,3-oxazolan-
5-ylmethyl}methylcarbamate or its salts;
(5S)-5-methylthioxy (thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-0xazolan-3-yl) phenyl]-1,3-oxazolan-2-one or its salts; N1-{(5S)-3-[3,5-difluoro-4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-2-oxo-1,3-oxazolan-5- ylmethyl} methyldithiocarbamate or its salts;
NI1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl}-2-oxo-1,3-0xazolan-5- ylmethyl} methylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4-(2-oxo-1,3-0xazolan-3-yl)phenyl]-2-o0xo0-1,3-oxazolan-5- ylmethyl} ethylthiocarbamate or its salts;
Ni- {(55)-3-[3-fluoro-4-(2-oxo-1,3-o0xazolan-3-yl)phenyl]-2-oxo- 1.3-o0xazolan-5-
ylmethyl} trifluoroacetoxythiocarbamate or its salts; (5S)-5-cyclohexyloxy (thioxo)methylaminomethyl-3-[4-(2-0x0-1 ,3-0xazolan-3-yl) phenyl]-1,3-oxazolan-2-one or its salts; NI- {(5S)-3-[3-fluoro-4-(2-thioxo-1 ,3-0xazolan-3-yl)phenyl]-2-0xo0-1,3-0xazolan-5- ylmethyl} methylthiocarbamate or its salts: N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1 -imidazolidinyl)phenyl]-2-oxo-1,3- oxazolan-5-ylmethyl} ethylthiocarbamate or its salts; N1-{(58)-3-[3-fluoro-4-(3-methyl-2-thioxo-1 -imidazolidinyl)phenyl]-2-0xo0-1,3-
oxazolan-5-ylmethyl}-1-propylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-thioxo-1 -imidazolidinyl)phenyl]-2-oxo-1,3- oxazolan-5-ylmethyl}methylthiocarbamate or its salts; N1-{(55)-3-[3-fluoro-4-(3-methyl-2-thioxo-1 -imidazolidinyl)phenyl]-2-oxo-1,3- oxazolan-5-ylmethyl}-2-propylthiocarbamate or its salts;
N1-{(55)-2-0x0-3-[4-(2-0x0-1 ,3-oxazolan-3-yl)-3-trifluoromethylphenyl]-1,3-oxazolan- 5-ylmethyl} methylthiocarbamate or its salts;
N1-{(5S)-2-o0x0-3-[4-(2-0x0-1,3-0xazolan-3 -yl)-3-trifluoromethylphenyl]-1,3-oxazolan- 5-ylmethyl} ethylthiocarbamate or its salts; N1-{(55)-3-[3,5-difluoro-4-(2-oxo0-1,3-oxazolan-3-yl)phenyl]-2-oxo-1,3-oxazolan-5- ylmethyl} methylthiocarbamate or its salts; NI1- {(55)-3-[4-(2-0x0- 1,3-oxazolan-3-yl)phenyl]-2-oxo0-1,3-oxazolan-5-ylmethyi} methyl thiocarbamate or its salts; : N1-{(58)-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-2-0x0-1,3-0xazolan-5 -ylmethyl} ethyl thiocarbamate or its salts; N1-{(5S)-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-2-oxo-1 ,3-oxazolan-5-ylmethyl} -1- propyl thiocarbamate or its salts; (58)-5-12,2,2-trifluoroethyloxy(thioxo)methylaminomethyi]-3-[4-(2-0xo0-1,3-0xa70lan- 3-yl) phenyl]-1,3-o0xazolan-2-one or its salts;
123 h (55)-5-[2-hydroxyethyloxy (thioxo)methylaminomethyl]-3-[{4-(2-ox0-1,3-0xazolan-3-yl) phenyl]}-1,3-oxazolan-2-one or its salts; (55)-5-[2-methoxyethyloxy (thioxo)methylaminomethyl]-3-[4-(2-0xo-1,3-oxazolan-3- yl) phenyl]-1,3-oxazolan-2-one or its salts;
NI1-{(5S)-3-[4-(2-0x0-1,3-0xazolan-3~yl)phenyl]-2-oxo-1 ,3-oxazolan-5-ylmethyl} allyithio carbamate or its salts; : N1-{(5S)-3-[4-(2-0x0-1,3-0xazolan-3-y)phenyl]-2-oxo-1,3-oxazolan-5-ylmethyl}-2- propylthio carbamate or its salts; N1-{(5S)-2-ox0-3-[4-(2-0x0-2,3-dihydrobenzo[d][1,3]Joxazol-3-yl)phenyl}-1,3-
oxazolan-5-ylmethyl} methylthiocarbamate or its salts; - N1-{(5S)-2-0x0-3-[4-(2-0x0-2,3-dihydrobenzo[d][1,3]oxazol-3-yl)phenyi]}-1,3- oxazolan-5-ylmethyl} ethylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4-(3-methyl-4-oxo-1-imidazolidinyl)phenyl]}-2-oxo-1,3-oxazolan- 5-ylmethyl} methylthiocarbamate or its salts;
NI1-{(5S)-3-[4-(3-methyl-2-0x0-1-imidazolidinyl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} methylthiocarbamate or its salts;
: N1-{(5S)-3-[4~(3-methyl-4-oxo-1-imidazolidinyl)phenyl}-2-oxo-1,3-0xazolan-5- ylmethyl} methylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4-(3-methyl-2-oxo-1-imidazolidinyl)phenyl]}-2-ox0-1,3-o0xazolan-
5-ylmethyl} methylthiocarbamate or its salts; N1-{(5S)-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} methylthiocarbamate or its salts; N N1-{(5S)-3-[4-(3-benzyl-2-oxo-1-imidazolidinyl)phenyl]-2-oxo-1,3-0xazolan-5- ylmethyl} ethylthiocarbamate or its salts;
'N1-{(5S)-3-[3-fluoro-4-(3-phenyl-2-oxo- 1-imidazolidinyl)phenyl]-2-oxo-1,3-0xazolan- 5-ylmethyl}methylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4-(3-phenyl-2-oxo-1-imidazolidinyl)phenyl}-2-oxo-1,3-oxazolan- 5-ylmethyl}ethylthiocarbamate or its salts;
. . PCT/INO1/00227 N1-((55)-3- {3-fluoro-4-[3-(4-fluorophenyl)-2-oxo- I-imidazolidinylJphenyl}-2-oxo-1,3- oxazolan-5-ylmethyl)methylthiocarbamate or its salts; N1-((55)-3-{3-fluoro-4-[3-(4-fluorophenyl)-2-oxo-1-imidazolidinyl]phenyl}-2-oxo-1,3- oxazolan-5-ylmethyl)ethylthiocarbamate or its salts; N1+(5S)-3-{3-fluoro-4-[3-(4-fluorophenyl)-2-oxo-1-imidazolidinyl Jphenyl } -2-0xo0-1,3- oxazolan-5-ylmethyl)-2-propylthiocarbamate or its salts; N1-((55)-3-{3-fluoro-4-[3-methoxymethyl-4-oxo-1-imidazolidinyl]phenyl} -2-oxo0-1,3- oxazolan-5-ylmethyl)methylthiocarbamate or its salts; N1-((55)-3- {3-fluoro-4-[3-bénzyl-4-oxo-1-imidazolidinyl]phenyl}-2-0x0-1,3-0xazolan- S-ylmethyl)methylthiocarbamate or its salts; : N1-((5S)-3-{3-fluoro-4-[3-benzyl-4-oxo-1-imidazolidinyiJphenyl}-2-0x0-1,3-0xazolan- 5-ylmethyl)ethylthiocarbamate or its salts;
. N1-((55)-3-{4-[2-0%0-1,3-0xazolan-3-yl]phenyl}-2-0x0-1,3-0xazolan-5-ylmethyl)- (N ,N-dimethylamino)ethylthiocarbamate or its salts. N1-((55)-3-{3-fluoro-4-[3-(4-methoxybenzyl)-4-oxo0-1-imidazolidinyl]phenyl}-2-oxo- 1,3-oxazolan-5-ylmethyl)methylthiocarbamate or its salts; . N1~((55)-3- {3-fluoro-4-[3-benzyl-4-oxo-1-imidazolidinyl phenyl} -2-oxo-1,3-0xazolan- 5-ylmethyl)isopropylthiccarbamate or its salts; ~~ N1+((5S)-3- {3-fluoro-4-[3-hydroxymethyl-4-oxo- 1-imidazolidinyl]phenyl} -2-0x0-1,3- © 20 oxazolan-5-yhmethyl)methyithiocarbamate or its salts; N1-((5S)-3-{3-fluoro-4-[4-oxo-1-imidazolidinyl]phenyl}-2-oxo-1,3-0xazolan-5- ylmethyl) methylthiocarbamate or its salts; N1-{(5S)-3-[3-fluoro-4~(3-methyl-4-thioxo-1-imidazelidinyl)phenyl]-2-oxo-1,3- : : oxazolan-5-ylmethyl} methylthiocarbamate or its salts; (55)-5-[(2S)-2-hydroxymethylazolan-1-yl(thioxo)methylaminomethyl]-3-[4-(2-ox0-1,3- oxazolan-3-yl)phenyl]-1,3-oxazolan-2-one or its salts; (5S)-5-diethylamino (thioxo)methylaminomethyl-3-[4-(2-oxo-1,3-0xazolan-3-yl) phenyl]-1,3-oxazolan-2-one or its salts; AMENDED SHEET :
. oo. PCT/INO1/00227 ) - (5S)-5-allylamino (thioxo)methylaminomethyl-3-{4-(2-0x0-1,3-0xazolan-3-yl)phenyl]- 1,3-oxazolan-2-one or its salts; (5S)-5-benzylamino(thioxo)methylaminomethy1-3-[4-(2-oxo-1,3-0xazolan-3-y1) phenyl]-1,3-oxazolan-2-one or its salts; 5- (55)-5-[4-methoxybenzylamino(thioxo)methylaniinomethyl]-3-[4-(2-0xo-1,3-oxazolan- 3-yDphenyl]-1,3-oxazolan-2-one or its salts; (5S)- 3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-5-[2-pyridylmethylamino (thioxo)methyl aminomethyl]-1,3-oxazolan-2-one or its salts; (5S)-5-methylamino (thioxo)methylaminomethyl-3-[4-(2-0x0-1,3-0xazolan-3-yl) phenyl]-1,3-0xazolan-2-one or its salts; | . (5S)-5-[2-hydroxyethylamino (thioxo)methylaminomethyl}-3-[4-(2-0x0-1,3-oxazolan-3- yD) phenyl}-1,3-oxazolan-2-one or its salts; (5S)- 3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-5-[ 1,4-thiazinan-4-yl (thioxo)methylamino methyl}-1,3-oxazolan-2-one or its salts; (5S)-3-[4-(2-0x0-1,3-0xazolan-3-yl)phenyl]-5-[2-pyridylamino (thioxo)methylamino methyl]- 1,3-oxazolan-2-one or its salts; oo (5S)-5-amino(thioxo)methylaminomethyl-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3- yDphenyl}-1,3-oxazolan-2-one or its salts; (5S)-3-[3-fluoro-4-(2-oxo-1,3-oxazolan-3-yl)phenyl]-5-methylamino(thioxo) methylamino methyl-1,3-oxazolan-2-one or its salts; (5S)-5-amino(thioxo)methylaminomethyl-3-[3,5-difluoro-4-(2-oxo-1,3-oxazolan-3- yDphenyl]-1,3-oxazolan-2-one or its salts; (55)-3-[3,5-diflioro-4-(2-oxo-1,3-0xazolan-3-yl)phenyl]-5-methylamino(thioxo)methy] ~ aminomethyl-1,3-oxazolan-2-one or its salts and N1-((5S)-3-{4-[2-0x0-1,3-0xazolan-3yl)phenyl}-2-oxo-1 »3-0xazolan-5-ylmethyl)- (N,N-dimethylamino)ethylthiocarbamate hydrochloride.
7. A compound according to claims 1 or 6, wherein the pharmaceutically acceptable : AMENDED SHEET
® salt is selected from Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases, chiral bases, natural amino acids, unnatural amino acids, substituted amino acids, guanidine, substituted guanidine salts; ammonium, substituted ammonium salts, aluminum salts and acid addition salts.
8. A process for the preparation of the compound of formula (I) ce £3 Za 0 @ s Y —Y 1s “rt where R' represents NHR®, wherein R* represents hydrogen atom; R? and R* are same or different and independently represent hydrogen, halogen atom, (C;-Ce)alkyl group, halo(C;-Cg)alkyl, cyano, nitro, SR?, NR*, OR? where R” represents substituted or unsubstituted (C;-Ce)alkyl group, or halo(C;-Ce)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (C,;-Cg)alkyl, (C;- - Cglalkenyl, (C,-Ce)cycloalkyl, (C;-Colalkoxy, aryl, aralkyl, aryloxy, (C;- Ce)alkylcarbonyl, arylcarbonyl, (C;-Cs)alkoxycarbonyl or aryloxycarbonyl; Y! represents =0 or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C,-Cgp)alkyl, hydroxy(C;-C¢)alkysl, (C1-Cy)alkoxy(C,-Cg)alkyl, (C;-Cg)alkoxycarbonyl, carboxy(C;-Co)alkyl, (C,-Cy)alkylsulfonyl, (Cy- Ce)alkylcarbonylamino(C,;-Ce)alkyl, arylcarbonylamino(C,-Cg)alkyl, (Ci- Ce)alkylcarbonyloxy(C;-Ce)alkyl, amino(C;-C¢)alkyl, mono(C,-Cs)alkylamino, di(C;- Ce)alkylamino, arylamino, (C;-C¢)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent _ carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: ® reacting a compound of formula (II)
v2 AN Z * NH 3 (IIT) where Y', Y2, Y? and Z are as defined above, with a compound of formula (IV) R? me: aw R3 where L represents a leaving group ; R* and R’ are as defined above, to produce a compound of formula V) R2 AN z n~{ Hno, (Y) v1 LS =: R3 where Y', Y2, Y? " R?, R? and Z are as defined above, (ii) reducing the compound of formula (V) to produce a compound of formula (VI)
m2.
YZ. NR Al Now _3 where Y!, Y2, YR, R} and Z are as defined above, (iii) reacting the compound of formula (VI) with alkylchloroformate, to produce a compound of formula (VII) R? Y? | fe) 2d Hymn VID) . yl =y3 =|: ORS : Rr3 where R¢ represents (C;-Cg)alkyl group group; YY, Y2, Y?, R%, R? and Z are as defined above, (iv) reacting the compound of formula (VII) with a compound of formula (VIII) 0) / \ 12 OR (VII) - Oo where R" represents (C,-C3) alkyl group in the presence of a base to produce a compound of formula (I) ut oo ANE Hen 0 ® yIE=ys pe “(rt where R' represents hydroxy; Y, v2, v3 R? R’ and Z are as defined above, (v) reacting the compound of formula (I) with alkylsulfonyl chloride or ary! sulfonyl chloride to produce a compound of formula (I), where R' represents alkyl sulfonyl or aryl sulfonyl, and reacted with NaN; to produce compound of formula (I) . i 2 Zz" n{ Hen 0 0) y=? yr — Rr where R! represents azido group; Yh Y?, Y?, R, R? and Z are as defined above and (vi) ‘reducing the compound of formula (I) where R' represents azido group, to produce a compound of formula (I) 2 x 1 EAE =a I yI=ys pe —(_r where R! represents NHR? wherein R* represnts hydrogen atom, Y', Y?, Y?, R?, R® and Z are as defined above.
9. A process for the preparation of compound of formula (I) y w? 5S ANd a 0 a) i YESS + (rt where R' represents hydroxy; R? and R® are same or different and independently represent hydrogen, halogen atom, (Cy-Ce)aikyl group, haio(Ci-Ce)aikyi, cyano, niiro, SR? NR?, OR? where R’ represents substituted or unsubstituted (C;-Ce)alkyl group, or halo(C;-Cglalkyl; Z represents S, O, =CH or NR® where R° represents hydrogen, or -
substituted or unsubstituted (C;-Cg)alkyl, (Ci-Ce)alkenyl, (C;-Cs)cycloalkyl, (Ci- Ce)alkoxy, aryl, aralkyl, aryloxy, (Ci-Cglalkylcarbonyl, arylcarbonyl, (Ci- Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y° independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Cealkyl, hydroxy(Ci-Cs)alkyl, (Ci-Ce)alkoxy(Ci-Ce)alkyl, (C;-Ce)alkoxycarbonyl, carboxy(C;- Ce)alkyl, (C1-Co)alkylsulfonyl, (C1-Ce)alkylcarbonylamino(C;-Ce)alkyl, arylcarbonylamino(C;-Co)atkyl, ~~ (Ci-Cg)alkylcarbonyloxy(C)-Ce)alkyl, amino(C;- Ce)alkyl, mono(C;-Ce)alkylamino, di(C;-Cs)alkylamino, arylamino, (C,-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y° when present on adjacent carbon atoms together may also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: (i) . reacting the compound of formula (VI) y ? ANd nn 429) yy =: R3 where YY? Y2, R%, R? and Z are as defined above, with a compound of formula (IX) Ar (IX) where R! represents hydroxy, to produce a compound of formula (X) eK ANd He OH ya + ~~ a X) where R represents hydroxy; YY YR, R® and Z are as defined above, and
(ii) carbonylating the compound of formula (X) with a carbonylating agent to produce the compound of formula (I) where R' represents hydroxy; Y', Y2, v3, RR? and Z ' are as defined above. :
10. A process for the preparation of compound of the formula (I) - Y2 il 1 ZO P ® Yr —Y ta —{_r where R' represents azido; R” and R’ are same or different and independently represent hydrogen, halogen atom, (C;-Cs)alkyl group, halo(Ci-Ce)alkyl, cyano, nitro, SR®, NR? OR? where R? represents substituted or unsubstituted (C,-Ce)alkyl group, or halo(C;- Cg)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (C;-Celalkyl, (Ci-Celalkenyl, (C,-Cg)cycloalkyl, (C-Cs)alkoxy, aryl, aralkyl, aryloxy, (C,-C¢)alkylcarbonyl, arylcarbonyl, (C 1-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =0 or =S group and Y? and Y* independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C,-Co)alkyl, hydroxy(C,-Ce)alkyi, (C;- Ce)alkoxy(C;-Ce)alkyl, (C,-Cs)alkoxycarbonyl, carboxy(C,;-C¢)alkyl, (C- Ce)alkylsulfonyl, (Ci-Ce)alkylcarbonylamino(C,-Ce)alkyl, arylcarbonylamino(C 1- Celalkyl, (C,-Cgalkylcarbonyloxy(C;-Cg)alkyl, amino(C:-Cs)alkyl, mono(C,- Cg)alkylamino, di(C,-Ce)alkylamino, arylamino, (C,-Cs)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y’ when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable soivates; which comprises: (1) reacting 2 compound of formula (VII)
od A © ZV'N NH y Ah = (VID) 3 } where R° represents (C,-Cs)alkyl group oup; vy! Y?, Y?, R? R® and Z are as defined } above, with a compound of formula (XI) XL XI) where L represents a leaving group; to produce a compound of formula (XII) fly CAN nd \ c Zz N N OR Era he (XII) Rr3 where R°, Y', Y2, Y3, R% R’ and Z are as defined above, (i) converting the compound of formula (XII) defined above to a compound of formula (XIII) . YZ x 1 “NN Zon Yn (XID VE =| —_, R® where Y', Y?, Y? , R?, R? and Z are as defined above, and - (iii) converting the compound of formula (XIII) defined above to a compound of formula (I) by reacting with organic or inorganic azide ; * 2 2nd Hn 0 0 Y= + Lr! where R' represents azido group; Y!, ¥2, Y3, R% R? and Z are as defined above.
11. A process for the preparation of compound of formula (I) oF % 20nd Hen 0 Mm y1L=ye + X “x where R! represents azido group; R? and R’ are same or different and independently represent hydrogen, halogen atom, (C;-Ce)alkyl group, halo(C,-Ce)alkyl, cyano, nitro, 5° SR? NR? OR? where R” represents substituted or unsubstituted (C1-Co)alkyl group, or halo(C;-Cg)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (C;-Cg)alkyl, (Cy-Ce)alkenyl, (C;-C¢)eycloalkyl, (C;- Ce)alkoxy, aryl, aralkyl, aryloxy, (C,-Ce)alkylcarbonyl, arylcarbonyl, (C;- Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y 2 and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C,;-Cg)alkyl, hydroxy(C:-Ce)alkyl, (C;-Cs)alkoxy(C;-Celalkyl, (C)-Ce)alkoxycarbonyl, carboxy(C,- Celalkyl, (C,-Cy)alkylsulfonyl, (C)-Co)alkylcarbonylamino(C,-Ce)alkyl, . arylcarbonylamino(C,-Cs)alkyl, (C,-Cs)alkylcarbonyloxy(C,-Ce)alkyl, amino(C,- Cglalkyl, mono(C;-Cg)alkylamino, di(C,-Ce)alkylamino, arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: (i) reacting a compound of formula (VII) : YZ ol | 0 AD, om "Rd oo :
where R° represents (C,-Cg)alkyl group; Y', Y?, v3, R?, R? and Z are as defined above, with a compound of formula (XVII) 0 XVID) where L represents leaving group; to produce a compound of formula (XVII)
or. i 0 ANd Nn ore YI =: (XVIII) _ rR? O where RS, Y!, Y2, Y?, R?, R’ and Z are as defined above, and (ii) converting the compound of formula (XVIII) defined above to a compound of formula (I), by reacting with an organic or an inorganic azide, . oi 2 AG, oe YY! —Y 13 “_r where R! represents azido group; Y!, Y?, v3 R% R? and Z are as defined above.
12. A process for the preparation of compound of formula (I) : Y2 x Jit oo Y' —Y Ls —(_r where R! represents hydroxy group; R? and R3 are same or different and independently represent hydrogen, halogen atom, (C1-Ce)alkyl group, halo(C;-Ce)alkyl, cyano, nitro, SR? NR? OR® where R® represents substituted or unsubstituted (C,-Ce)alkyl group, or halo(C1-Ce)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (Ci-Co)alkyl, (Cz-Cojalkenyl, (Ci-Ceeycloalkyl, (Ci- Ce)alkoxy, aryl, aralkyl, aryloxy, (C1-Cg)alkylcarbonyl, arylcarbonyl, (C;- . Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y? independently represent. hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, : =S group, or substituted or unsubstituted groups selected from (C;-Ce)alkyl,
hydroxy(Ci-Ce)alkyl, (Ci-Cs)alkoxy(Ci-Ce)alkyl, (Ci-Co)alkoxycarbonyl, carboxy(C,- Ce)alkyl, (Cy-Ce)alkylsulfonyl, | (Ci-Co)alkylcarbonylamino(C;-Cg)alkyl, arylcarbonylamino(C,;-Ce)alkyl, (Ci-Cealkylcarbonyloxy(C,-Ce)alkyl, amino(C;- Ce)alkyl, mono(C;-Ce)alkylamino, di(C,-Cg)alkylamino, arylamino, (C 1-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or "unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: @) reacting a compound of formula (VII) : vz ol o 20-0 Hn VID y= ys =| OR® : rR : where R® represents (C;-Cg)alkyl group; Y', Y?, Y>, R% R® and Z are as defined above, with a compound of formula (XIV) $s (XIV) 5 | SANG where L represents a leaving group; to produce a compound of formula XV) : y i 0 ANd Hnore HES? =| Lo (XV) R3 O a where R° represents (C;-Cg)alkyl group; Y!, Y2, Y? , R?, R? and Z are as defined above, (ii) | hydrolysing the acetonide moiety in the compound of formula (XV) to produce a compound of formula (XVI) .
y ia 0 ANd Snore yi a =: XVID) R3 OH : - where R®, Y', Y?, Y?, R?, R® and Z are as defined above, and (i) cyclising the compound of formula (XVI) with or without a base to a compound of formula (I), where R! represents hydroxy group; Y', Y?, Y?, R% R® and Z are as defined above.
13. A process for the preparation of compound of the formula MD Fa 20:0 NP ® Y' —Y ls (gt where R! represents NHR’, wherein R* represents acetyl group; R? and R? are same or different and independently represent hydrogen, halogen atom, (C,-Cg)alkyl group, halo(C,-Cs)alkyl, cyano, nitro, SR, NR?, OR® where R® represents substituted or "unsubstituted (C;-Ce)alkyl group, or halo(C)-Ce)alkyl; Z represents S, 0, =CH or NR" where R® represents hydrogen, or substituted or unsubstituted (C1-Ce)alkyl, (C,- Ce)alkenyl, (C;-Cs)cycloalkyl, (Ci-Co)alkoxy, aryl, aralkyl, aryloxy, (C;- Ce)alkylcarbonyl, arylcarbonyl, (Cy-Cg)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y* and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Cg)alkyl, hydroxy(C;-Ce)alkyl, (C1-Ce)alkoxy(C;-Cq)alkyl, (C1-Cg)alkoxycarbonyl, carboxy(C;-Cg)alkyl, (Cy-Ce)alkylsulfonyl, (Cs- Cé)alkylcarbonylamino(C,-Cealkyl, arylcarbonylamino(C,-Ce)alkyl, Cs- Cs)alkylcarbonyloxy(C,-Ce)alkyl, amino(C,-Cs)alkyl, mono(C;-Cs)alkylamino, di(Cy- Ce)alkylamino, arylamino, (C,-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y> and Y® when present on adjacent ’ carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; Its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: : (i) reacting a compound of formula (VII) eo Fo Aal)- wo ID R® where R® represents (C;-Cg)alkyl group; Y!, Y2 Y3, R% R® and Z are as defined above, with a compound of formula (XIX) 0] H . : EAN He XIX) . 0 to produce a compound of formula (I) YZ R 1 | - 0 Y —Y La rw - where R' represents NHR, wherein R? represents acetyl group; Y', Y%, Y°, R%, Rand Z are as defined above.
14. A process for the preparation of compound of formula (I) oe AR EEN Ye +: —_r where R' represents NHR, wherein R* represents formyl group; R” and R? are same or different and independently represent hydrogen, halogen atom, (C;-Cs)alkyl group, halo(C;-C¢)alkyl, — nitro, SR?, NR?, OR® where R? represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C,-Cg)alkyl; Z represents S, O, =CH or NRP where R° represents hydrogen, or substituted or unsubstituted (C;-Celalkyl, (Cp- . Cgalkenyl, (C;-Ce)cycloalkyl, (Ci-Cs)alkoxy, aryl, aralkyl, aryloxy, (C-
Ce)alkylcarbonyl, arylcarbonyl, (C;-Cs)alkoxycarbonyl or aryloxycarbonyl; Y! represents. =O or =S group and Y* and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Ce)alkyl, hydroxy(C,;-Ce)alkyl, (C;-Cs)alkoxy(C;-Cs)alkyl, (Ci-Ce)alkoxycarbonyl, carboxy(C;-Cg)alkyl, (C1-Ce)alkylsulfonyl, (Cy- Ce)alkylcarbonylamino(C;-Cg)alkyl, arylcarbonylamino(C,-Ce)alkyl, (Ci- Cs)alkylcarbonyloxy(C;-Ce)alkyl, amino(C;-Cg)alkyl, mono(C;-Ce)alkylamino, di(C;- Ce)alkylamino, arylamino, (C,-Cg)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y* when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; which comprises: formylating the compound of formula (I) where R' represents NHR* wherein R* represents hydrogen and Y', Y? Y?, R% R® and Z are as defined above, by using alkylformate.
15. A process for the preparation of compound of formula (I) ve 2 | oo 2nd Meg : y1IE=ys + —{_ R! where R' represents NHR*, wherein R* represents —C(=0)-R*, wherein R* represesnts (C-Cg)alkyl, (C,-Cglalkoxy, (C;-Ce¢)alkenyl, halo(Ci-Cg)alkyl, aryloxy, (C»- Ce)alkenyloxy, aryloxycarbonyl or (C;-C¢)alkoxycarbonyl; R? and R® are same or different and independently represent hydrogen, halogen atom, (C;-Ce)alkyl group, halo(C;-Cg)alkyl, cyano, nitro, SR?, NR’, OR" where R*® represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C;-Cg)alkyl; Z represents S, O, =CH or NR" where R® represents hydrogen, or substituted or unsubstituted (C;-Ce)alkyl, (C,- Ce)alkenyl, (C;-Ce)cycloalkyl, (Ci-C¢)alkoxy, aryl, aralkyl, aryloxy, (C- 15 Cgalkylcarbonyl, arylcarbonyl, (Ci-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, : cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Ce)alkyl, hydroxy(C,-Ce)alkyl, (C;-Cg)alkoxy(C,-Cq)alkyl, (C1-Cg)alkoxycarbonyl, carboxy(C;-Cq)alkyl, (Ci-C)alkylsulfonyl, (Ci- .Ce)alkylcarbonylamino(C,-Ce)alkyl, arylcarbonylamino(C,-Cy)alkyl, (Cr- : Cg)alkylcarbonyloxy(C;-Ce)alkyl, amino(C,-Cealkyl, mono(C,-Cg)alkylamino, di(C,- Cg)alkylamino, arylamino, (C,-Cg)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y® when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; which comprise: acetylating the compound of formula (I) where R! represents NHR* wherein R* represents hydrogen; Y!, Y2, v3 , R?, Rand Z are as defined above, by using a halide.
16. A process for the preparation of compound of formula (I) YZ i 1 200 Hn ® YY + rw where R' represents NHR®, wherein R* represents acetyl group; R? and R? are same or different and independently represent hydrogen, halogen atom, (C;-C¢)alkyl group, halo(C,-Ce)alkyl, cyano, nitro, SR, NR? OR® where R* represents substituted or unsubstituted (C;-Cs)alkyl group, or halo(C;-Cs)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (C;-C¢)alkyl, (C,- © Coalkenyl, (Ci-Ce)cycloalkyl, (Ci-Ce)alkoxy, aryl, aralkyl, aryloxy, (Ci- Ce)alkylcarbonyl, arylcarbonyl, (C;-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y? and Y® independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C,-Ce)alkyl, hydroxy(C,-Ce)alkyl, (Ci-Cs)alkoxy(C,-Ce)alkyl, (C:-Ce)alkoxycarbonyl, carboxy(C-Ce)alkyl, (C-Ce)alkylsulfonyl, (Cy- Cg)alkylcarbonyiamino(Ci-Ce)alkyl, aryicarbonylawiuo{Ci-Cejalkyl, (Ci Ce)alkylcarbonyloxy(C;-Cg)alkyl, amino(Cy-Celalkyl, mono(C;-Cglalkylamino, di(Ci- Ce)alkylamino, arylamino, (Ci-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, :
heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y® when present on adjacent .carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its “stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: reacting compound of formula (I) where R' represents azido group; Y', YZ, Y3, R%, R> and Z are as defined above, with thioacetic acid.
17. A process for the praparation of compound of formula (I) a FR 2 Hn vy yr Ur © where R' represents NHR*, wherein R* represents —C(=S)-R*®, wherein RP represents (Cy-Ce)alkyl, halo(C;-Cglalkyl, -C(=0)-(C;-Cg)alkoxy, -C(=0)-aryloxy, -C(=S)-(C)- Ce)alkyl or -C(=S)-aryl; R* and R’ are same or different and independently represent hydrogen, halogen atom, (C,-Cg)alky! group, halo(C;-Cg)alkyl, cyano; nitro, SR®, NR? OR* where R" represents substituted or unsubstituted (C,-C¢)alkyl group, or halo(Ci- . Cg)alkyl; Z represents S, O, =CH or NR® where R? represents hydrogen, or substituted or unsubstituted (C,-Cg)alkyl, (C-Cs)alkenyl, (C;-Cs)cycloalkyl, (Cy-Ce)alkoxy, aryl, aralkyl, aryloxy, (C;-Cealkylcarbonyl, arylcarbonyl, (Cy-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Cg)alkyl, hydroxy(C;-Ce)atkyl, (C;- Ce)alkoxy(C;-Ce)alkyl, (Ci-Ce)alkoxycarbonyl, carboxy(C;-Ce)alkyl, (Ci- Celalkylsulfonyl, (C,-Cg)alkylcarbonylamino(C;-Ce)alkyl, arylcarbonylamino(C;- Ce)alkyl, (C,-Ce)alkylcarbonyloxy(C-Cy)alkyl, amino(C,-Ce)alkyl, mono(C;- Cs)alkylamino, di(C;-Cs)alkylamino, arylamino, (C,-Ce)alkoxy, aryl, aryloxy, aralkyl, ) 25 heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl, Y? and Y? when present on adjacent carbon atoms together also formi a substituted or unsubstituted 5 or 6 - membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable - solvates; which comprises: reacting the compound of formula (I) where R' represents NHR*, wherein R* represents ~C(=0)-R™, wherein R*® represents (C;-Cg)alkyl,halo(C,- Cealkyl, -C(=0)-(C,-Ce)alkoxy, -C(=O)-aryloxy, -C(=S)-(C,-Ce)alkyl or -C(=S)-aryl; Y!, Y2 Y?, R? R3and Z are as defined above, with 2,4-bis(methoxyphenyl)-1,3-dithia- 2,4-diphosphetane-2,4-disulfide (Lawesson’s reagent).
18. A process for the preparation of compound of formula (I) Y2 il 1 NOES: the I I where R' represents NHR®, wherein R* represents —C(=S)-SR* wherein (Cy-Ce)alkyl group; R* and R® are same or different and independently represent hydrogen, halogen atom, (C;-Ce¢)alkyl group, halo(C,-Ce)alkyl, cyano, nitro, SR?, NR? OR? where R* represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C;-Cg)alkyl; Z represents S, O, =CH or NR" where R® represents hydrogen, or substituted or unsubstituted (Ci-Cq)alkyl, (C,-Ce)alkenyl, (C;-Ce)cycloalkyl, (C,-Cg)alkoxy, aryl, aralkyl, aryloxy, (C;-Cs)alkylcarbonyl, arylcarbonyl, (C,-Cs)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y* and Y independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =0, =S group, or substituted or unsubstituted groups selected from (C;-Cgalkyl, hydroxy(Ci-Cé)alkyl, (Ci- Co)alkoxy(C;-Ce)alkyl, (Ci-Ce)alkoxycarbonyl, carboxy(C,-Cs)alkyl, (or Ce)alkylsulfonyl, (C;-Cs)alkylcarbonylamino(C,-C¢)alkyl, arylcarbonylamino(C;- Celalkyl, (C;-Cg)alkylcarbonyloxy(C,-Ce)alkyl, amino(C,-Cg)alkyl, mono(C,- Cs)alkylamino, di(C,-C¢)alkylamino, arylamino, (C;-C¢)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y> when present on adjacent carbon atoms together aiso form a substituied or unsubsiiluied 5 or © membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable . solvates; which comprises: reacting the compound of formula (I) where R' represents ) NHR", wherein R? represents hydrogen; vY!, Y?, Y3, rR? R? and Z are as defined above, by reacting with carbondisulfide, with an appropriate alkylhalide and a base selected from Et;N, diisopropylethylamine, K,COs;, NaH or KOt-Bu.
19. A process for the preparation of compound of formula (I) y it 2 2 no yey +: —(_ rR’ D where R! represents NHR*, wherein R* represents ~C(=S)-OR™, wherein R* represents (Ci-Cg)alkyl, cyclo(Cs-Cg)alkyl, ~(C=0)-(C,-Cg)alkyl group substituted with fluorine, aryl, , halo(Ci-Cealkyl, hydroxy(C;-Cs)alkyl, (C;-Cs)alkoxy(C;-Ce)alkyl or (Cs Cg)alkenyl; R* and R® are same or different and independently represent hydrogen, halogen atom, (C;-Cg)alkyl group, halo(Ci-Cs)alkyl, cyano, nitro, SR*, NR? OR? where R? represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C;-Cy)alkyl; Z represents S, O, =CH or NR” where RP represents hydrogen, or substituted or unsubstituted (C,-Cglalkyl, (C-Celalkenyl, (C,-Ce)eycloalkyl, (Ci-Ce)alkoxy, aryl, aralkyl, aryloxy, (C,-C¢)alkylcarbonyl, arylcarbonyl, (C;-Ce)alkoxycarbonyl or * aryloxycarbonyl; Y' represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted . or unsubstituted groups selected from (Ci-Co)alkyl, hydroxy(C;-Cg)alkyl, (C;- Cgalkoxy(Ci-Ce)alkyl, .” (C;-Ce)alkoxycarbonyl, carboxy(C;-Cg)alkyl, (Cs- Ce)alkylsulfonyl, (C;-Cg)alkylcarbonylamino(C;-Cs)alkyl, arylcarbonylamino(C,- Ce)alkyl, (Ci-Cg)alkylcarbonyloxy(C;i-Ce)alkyl, amino(C,-Ce)alkyl, mono(C;- Ce)alkylamino, di(C;-Ce)alkylamino arylamino, (Cy-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two : hetero atoms; its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: (i) converting compound of formula (I) where R! represents NHR?, wherein R* ’ represents hydrogen atom; Y', Y?, Y?, R? R’ and Z are as defined above, to a compound of formula (I) where R! represents isothiocyanate group and all other symbols are as defined above, by reacting with thiophosgene and ’ (ii) converting compound of formula (I) where R! represents isothiocyanate group, to a compound of formula (I) where R' represents NHR*, wherein R* represents —C(=S)- OR™, wherin R* represents (C;-Cs)alkyl, cyclo(C3-Ce)alkyl, (C=0)~(C,-Ce)alkyl group substituted with fluorine, aryl, , balo(Ci-Cealkyl, hydroxy(C,-Ceakkyl, (Ci- Ce)alkoxy(C;-Ce)alkyl or (C-Ce)alkenyl and all symbols are as defined above, by reacting with alcohol.
20. A process for the preparation of compound of formula (I) : 2 x 1 7n Hn 0 o YIE=ye pe “_r where R' represents NHR*, wherein R® represents - —C(=S)-N(R’R”), R’ represents hydrogen, (C;-Cs)alkyl, (C2-Ce)alkenyl, substituted or unsubstituted aralkyl, heteroaralkyl, hydroxy(C;-Ce)alkyl, R” represents hydrogen or (C1-Cg)alkyl or R’ and R” together form a 5 or 6 membered cyclic structures containing one or two hetero atoms; R? and R® are same or different and independently represent hydrogen, halogen atom, (C,-Ce)alkyl group, halo(C;-Ce)alkyl, cyano, nitro, SR? NR? OR? where R* represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C,-Ce)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (C;-Ce)alkyl, (Cz-Ce)alkenyl, (Ci-Cg)cycloalkyl, (Ci-Ce)alkoxy, aryl, aralkyl, aryloxy, (Cy-Ce)alkylcarbonyl, arylcarbonyl, (Ci-Cg)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y and V2 independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Celalkyl, hydroxy(Ci-Ce)alkyl, (Ci-
Ce)alkoxy(C,-Cg)alkyl, (C;-Ce)alkoxycarbonyl, carboxy(C,;-Ce)alkyl, (Cs- Ce)alkylsulfonyl, (C;-Cgs)alkylcarbonylamino(C;-Ce)alkyl, arylcarbonylamino(C;- i Cealkyl, (C;-C¢)alkylcarbonyloxy(C;-Ce)alkyl, amino(C,-Cs)alkyl, mono(C,- Ce)alkylamino, di(C;-Cs)alkylamino, arylamino, (C,-Cg)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y® when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms its ‘derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: converting compound of formula (I) where R' represents isothiocyante group and all other symbols are as defined above by passing ammonia gas or by reacting with amine.
21. A novel interinediate of formula (VII) vz ol 0 R3 where R° represents (C;-Cg)alkyl group ; R? and R® are same or different and independently represent hydrogen, halogen atom, (C,-Cs)alkyl group, halo(C,-Ce)alkyl, cyano, nitro, SR? NR’ OR® where R? represents substituted or unsubstituted (C;- Ce)alkyl group, or halo(C-Ce)alkyl; Z represents S, O, =CH or NR’ where R® represents hydrogen, or substituted or unsubstituted (C;-Ce)alkyl, (C2-Ce)alkenyl, C- Cg)cycloalkyl, (C,-Ce)alkoxy, aryl, aralkyl, aryloxy, (C,-Ce)alkylcarbonyl, arylcarbonyl, (C;-Ce)alkoxycarbonyl or aryloxycarbonyl; Y! represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =0, =S group, or substituted or unsubstituted groups selected from (C;-Cealkyl, hydroxy(C;-Ce)alkyl, (C,-Ce)alkoxy(Ci-Ce)alkyl, (Ci-Ce)alkoxycarbonyl, carboxy(C;- Celalkyl, (C,-Ce)alkylsulfonyl, (C;-Cg)alkylcarbonylamino(C,;-Ce)alkyl, arylcarbonylamino(C;-Cs)alkyl, (C1-Cg)alkylcarbonyloxy(Ci-Ce)alkyl, amino(C;- } Ce)alkyl, mono(C;-Cg)alkylamino, di(C;-Ce)alkylamino, arylamino, (Ci-Ce)alkoxy, aryl,
aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y> when present on adjacent carbon atoms together also form a substituted or unsubstituted or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or i two hetero atoms. 5
22. Aprocess for the preparation of compound of formula (VII), claimed in claim 21 R2 v2 0 ANE a VID yI=Sys =| = OR® R3 Y', YY’, R, R?, R? and Z are as defined in claim 21, which comprises: 6) reacting a compound of formula (III) v2 RY i Z * NH ys a where Y', Y2, Y* and Z are are as defined in claim 21, with a compound of formula (IV) RZ es av) . ip where L represents a leaving group; R? and R> are as defined in claim 21, to produce a compound of formula (V) R2 AAR 7 nd Hero, \%) 13 = R3 where Y', Y?, ¥?, R%, R? and Z are as defined defined in claim 21, (ii) reducing the compound of formula (V) to produce a compound of formula (VI) R2 oie ZN H - wir Na == 2 (VI) Y T Rr? where Y', YZ, Y°, R?, R® and Z are as defined defined in claim 21,
(iif) reacting the compound of formula (VI) with alkylchloroformate, to produce a compound of formula (VID) 2 Fl Ned? ys =: ORS (Vin R3 where R° represents (C;-Cg)alkyl group; Y', Y?, Y°, R?, R® and Z are as defined in claim
21.
23. A novel intermediate of formula (VI) 2 RS a ERehal VD R® : where R? and R® may be same or different and independently represent hydrogen, halogen atom, (C,-Cg)alkyl group, halo(C;-C¢)alkyl, cyano, nitro, SR®, NR?, OR® where R® represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C,-Cg)alkyl; Z represents S, O, =CH or NR? where R® represents hydrogen or substituted or unsubstituted (C;-Cg)alkyl, (C;-C¢)alkenyl, (C1-Co)cycloalkyl, (C,-Ce)alkoxy, aryl, aralkyl, aryloxy, (C,-Cg)alkylcarbonyl, arylcarbonyl, (C,-Cs)alkoxycarbonyl or g aryloxycarbonyl; Y' represents =O or =S group; Y? and Y* independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group or substituted or unsubstituted groups selected. from (C;-Cg)alkyl, hydroxy(C;-Cslalkyl, (C;- Cs)alkoxy(C,-Ce)alkyl, (Ci-Ce)alkoxycarbonyl, carboxy(C;-Ce)alkyl, (C;- Co)alkylsulfonyl, (C,-Ce)alkylcarbonylamino(C;-Ce)alkyl, arylcarbonylamino(C;- Ce)alkyl, (Ci-Co)alkylcarbonyloxy(Ci-Cg)alkyl, amino(C,-C¢)alkyl, mono(C;- Cg)alkylamino, di(C;-C¢)alkylamino, arylamino, (C,-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y® when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 ‘ membered aromatic or non-aromatic cyclic structure, containing one or two hetero atoms. :
24. A process for the preparation of compound of formula (VI), claimed in claim 23
YZ. RN . z\ nd Hn H, VD ys =x R3 Y', Y% Y?, R%, R? and Z are as defined in claim 23, which comprises: 3) reacting a compound of formula (III) Y?2 AN : . Z * NH yl Sy3 (1m where Y', Y2, Y? and Z are are as defined in claim 23, with a compound of formula (IV) oo Re —{ ba av) : Ra where L represents a leaving group; R* and R? are as defined in claim. 23, to produce a compound of formula (V) Rr? :
YZ. z\ nd Vno, v) vy! ZN v3 = R® where Y', YY? RY, R> and Z are as defined in claim 23, and (i) reducing the compound of formula.(V) to produce a compound of formula (VI) Rr? YZ, oz nd Hen (VD 1X3 =f R® where Y', Y2, Y3, R?, R3 and Z are as defined in claim 23.
25. A novel intermediate of formula (X) Co oo R2 YZ 7nd Hn OH v? XS =x ~~ xX) R® R'
where R' represents halo, azido, isothiocyanate, thioalcohol, OR*, NHR* or NR, where R* represents hydrogen atom, or substituted or unsubstituted groups selected from acyl, thioacyl, (C;-Cg)alkoxycarbonyl, (C;-Cg)cycloalkoxythiocarbonyl, (Cs- Ce)alkenyloxycarbonyl, (C3-Ce)alkenylcarbonyl, aryloxycarbonyl, (Cy- Cealkoxythiocarbonyl, (C,-Cs)alkenyloxythiocarbonyl, aryloxythiocarbonyl, -C(=0)- C(=0)-alkyl, -C(=0)-C(=0)-aryl, -C(=0)-C(=O)-alkoxy, -C(=0)-C(=O)-aryloxy, - (C=S)-S-alkyl, -(C=S)-NH,, -(C=S)-NH-alkyl, -C(=S)-N-(alkyl);, -C(=S)-NH-alkenyl, : (C=S)-(C=0)-alkoxy, -(C=S)-(C=0)-aryloxy, -C(=S)-O-(C=0)-alkyl, C(=S)-C(=S)- alkyl, -C(=S)-C(=S)-aryl, thiomorpholinylthiocarbonyl or pyrrolidinylthiocarbonyl; R> and R® are same or different and independently represent hydrogen, halogen atom, (C;- Ce)alky! group, halo(C;-Ce)alkyl, cyano, nitro, SR?, NR?, OR* where R? represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C,-Cs)alkyl; Z represents S, O, =CH or NR" where R® represents hydrogen, or substituted or unsubstituted (C;-Cg)alkyl, (C2-Ce)alkenyl, (C;-Cg)eycloalkyl, (C,-Celalkoxy, aryl, aralkyl, aryloxy, (C;- Cg)alkylcarbonyl, arylcarbonyl, (C;-Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y° independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted ’ groups selected from (C1-Co)alkyl, hydroxy(C,-Ce)alkyl, (C;-Ce)alkoxy(C;-Ce)alkyl, (C;-Ce)alkoxycarbonyl, carboxy(C;-Cg)alkyl, (Cy-Cg)alkylsulfonyl, (Cs- Cealkylcarbonylamino(C;-Cg)alkyl, “arylcarbonylamino(Ci-Co)alkyl, (Cy- Cs)alkylcarbonyloxy(C,-Cg)alkyl, amino(C,-Ce)alkyl, mono(C,-Cg)alkylamino, di(C,- Ce)alkylamino, arylamino, (C;-Cg)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms.
26. A process for the preparation of compound of formula (X), claimed in claim 25 R2 v2 Z nd Henn OH YA ye \afs ~ x) oo | R3 Rr . where R', Y', Y?, Y°, R%, R® and Z are as defined in claim 25, which comprises: 1) reacting a compound of formula (IIT) :
. v2 ’ ND Z NH . ys a where Y', Y2, Y® and Z are as defined in claim 25, with a compound of formula Tv R? (Dre: av) R3 where L represents a leaving group; R* and R? are as defined in claim 25, to produce a compound of formula (V) R2 v2. z\ nd to, v) vy! 3 = R® where Y', Y?, Y3, R?, R® and Z are as defined in claim 25, (i) reducing the compound of formula (V) to produce a compound of formula (VI) R2
YZ. z\ n= Drm, (VD v1 oN v3 =: where Y', Y?, Y? ,R?, R? and Z are as defined in claim 25, and (ii) reacting the compound of formula (VI) with a compound of formula (IX) 0) / \ “ YON = _R (EP: §) where R' is as defined in claim 25. .
27. A novel intermediate of formula (XVI) Co . v2 x 9 zn Honor y1 3 =| = (XVI) . RrR3 OH where R® represents (C,-Cs)alkyl group; R? and R’ are same or different and independently represent hydrogen, halogen atom, (C;-C¢)alkyl group, halo(C;-Cg)alkyl, cyano, nitro, SR? NR?, OR? where R? represents substituted or unsubstituted (Cs- Cs)alkyl group, or halo(C,-Cg)alkyl; Z represents S, O, =CH or NR? where R® represents hydrogen, or substituted or unsubstituted (C,-Ce)alkyl, (C,-Ce)alkenyl, (C,;- Ce)cycloalkyl, (C;-Cg)alkoxy, aryl, aralkyl, aryloxy, (C;-Cs)alkylcarbonyl, arylcarbonyl, . (C\-Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =0, =S group, or substituted or unsubstituted groups selected from (C;-Cg)alkyl, hydroxy(C;-Ce)alkyl, (Ci-Ce)alkoxy(C;-Ce)alkyl, (C;-Cs)alkoxycarbonyl, carboxy(C;- Ce)alkyl, (C-Ce)alkylsulfonyl, (C1-Ce)alkylcarbonylamino(C;-Cg)alkyl, arylcarbonylamino(C,-Ce)alkyl, (C;-C¢)alkylcarbonyloxy(C,;-C¢)alkyl, amino(C;- Cglalkyl, mono(C,-Cg)alkylamino, di(C;-Ce)alkylamino arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted © 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms.
28. A process for the preparation of compound of formula (XVI), claimed in claim 27 Y2 hl a. oo Fad Hore y1ES3 =| Sd XVI) Rr? OH where R°, Y' ¥2 Y3 R% R’ and Z are as defined in claim 27, which comprises: . (i) reacting a compound of formula (VII) }
R2 a YZ | e) : PO A ZN NH vy! LB = = ) ] , R® where R®, Y', Y?, Y?, R?, R? and Z are as defined in claim 27, with a compound of formula (XIV) >So (XIV) L _— where L represents a leaving group; to produce a compound of formula (XV) ) R?. 0) 2 Yn or v1 NB =| XV) RG 5 0 A where RS, Y', Y2, Y°, R?, R? and Z are as defined in claim 27, and (ii) hydrolysing the acetonide moiety in the compound of formula (XV) using conventional methods to produce a compound of formula (XVI) YZ i i 2nd ore PEIN OH (XVI) rR? OH oo where RS, Y', Y2, Y2, R%, R? and Z are as defined in claim 27.
29. A novel intermediate of formula (XVIII) y ° znd Nore pia Nae (XVIII RS © where R® represents (C;-Csg)alkyl group; R? and R’ are same or different and independently represent hydrogen, halogen atom, (C;-Ce)alkyl group, halo(C,-Ce)alkyl, : cyano, nitro, SR?, NR?, OR* where R® represents substituted or unsubstituted (C,-
» Ce)alkyl group, or halo(C,-Cg)alkyl; Z represents S, O, =CH or NR? where R® represents hydrogen, or substituted or unsubstituted (C;-Cg)alkyl, (Cy-C¢)alkenyl, (C;- Ce)cycloalkyl, (C;-Cg)alkoxy, aryl, aralkyl, aryloxy, (C;-Cs)alkylcarbonyl, arylcarbonyl, (C1-Cs)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, ~ =0, =S group, or substituted or unsubstituted groups selected from (C,-Cg)alkyl, hydroxy(C;-Ce)alkyl, (Ci-Cs)alkoxy(C-Ce)alkyl, (C;-Cg)alkoxycarbonyl, carboxy(C,- Ce)alkyl, (Ci-Ce)alkylsulfonyl, (C1-Ce)alkylcarbonylamino(C,-Ce)alkyl, arylcarbonylamino(C,-Cg)alkyl, (C,-Cs)alkylcarbonyloxy(C;-C¢)alkyl, amino(C,- Cg)alkyl, mono(C;-Ce)alkylamine, di(C,-Cs)alkylamino, arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted ~ 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms. :
30. A process for the preparation of compound of formula (XVIII), claimed in claim 29 BE 2 ol o) ANd Den More yy Nf: Le (VID R3 lo) i. where R%, Y', YZ, Y>, R%, R? and Z are as defined in claim 29, which comprises: reacting a compound of formula (VII) 2 R? Y, | 0 Eanadie NHS ee OVID rR’ oo where R®, Y', Y2 Y?, R% R’ and Z are as defined in claim 29, with a compound of formula (XVII) : | oo . 0 (XVII) . .
-~ 152 PCT/INO01/00227 where L represents a leaving group; to produce a compound of formula (XVIII), where RS, Y', YY? R? R® and Z are as defined in claim 29. : 2 R? Q Nore YS 3 =| L (XVI) BE yg where RS, Y', Y2, Y>, R% R’ and Z are as defined in claim 29.
31. A pharmaceutical composition comprising a compound of formula (J) Cp Re } 1 ANE Hn 0 ® yi + a as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
32. A pharmaceutical composition as claimed in claim 31, in the form of a tablet, capsule, powder, syrup, solution or suspension. :
33." Use of a compound of formula (I) as claimed in claim 1 in the manufacture of a preparation for treating a bacterial infection.
34. A substance or composition for use in a method of treating a bacterial infection, said substance or composition comprising a compound of formula (I) as claimed in claim 1, and said method comprising administering said substance or composition to a subject.
35. A pharmaceutical composition comprising a compound as claimed in claim 6 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
36. A pharmaceutical composition as claimed in claim 35, in the form of a tablet, capsule, powder, syrup, solution or suspension.
37. Use of a compound as claimed in claim 6 in the manufacture of a preparation for treating a bacterial infection.
38. A substance or composition for use in a method of treating a bacterial infection, said substance or composition comprising a compound as claimed in claim 6, and said method comprising administering said substance or composition to a subject. AMENDED SHEET
39. A process for the preparation of compound of formula (1), Y2 x 1 . AN { Hn ° ® Si +; =r where Z represents NR® wherein R® represents hydrogen, Y' represents ‘=0’ group, Y> and Y? independently represent hydrogen atom, R! represents halo, azido, isothiocyanate, thioalcohol, OR*, NHR" or N(RH, where R* represents hydrogen atom, or substituted or unsubstituted groups selected from acyl, thioacyl, (C- Ce)alkoxycarbonyl, (C3-Ce)eycloalkoxythiocarbonyl, (C2-Ce)alkenyloxycarbonyl, (C,- Ce)alkenylcarbonyl, aryloxycarbonyl, (Ci-Cg)alkoxythiocarbonyl, (Cs- Ce)alkenyloxythiocarbonyl, aryloxythiocarbonyl, -C(=0)-C(=0)-alkyl, -C(=0)-C(=0)- aryl, -C(=0)-C(=0)-alkoxy, -C(=0)-C(=0)-aryloxy, -(C=S)-S-alkyl, -(C=S)-NH,, - (C=S)-NH-alkyl, -C(=5)-N-(alkyl);, -C(=S)-NH-alkenyl, (C=8)-(C=0)-alkoxy, -(C=S)- (C=0)-aryloxy, -C(=S)-O-(C=0)-alkyl, C(=S)-C(=S)-alkyl, -C(=S)-C(=S)-aryl, thiomorpholinylthiocarbonyl or pyrrolidinylthiocarbonyl; R? and R® may be same or different and independently represent hydrogen, halogen atom, (C1-Co)alkyl group, halo(C;-Ce)alkyl, cyano, nitro, SR? NR? OR? where R® represents substituted or unsubstituted (Cy-Cg)alkyl group, or halo(C;-Cealkyl: Z represents S, O, =CH or NR? where R® represents hydrogen or substituted or unsubstituted (Ci-Ce)alkyl, (C,- Cealkenyl, (C;-Cg)cycloalkyl, (C-Colalkoxy, aryl, aralkyl, aryloxy, (C;- Ce)alkylcarbonyl, arylcarbonyl, (C1-Co)alkoxycarbony] or aryloxycarbonyl its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: reacting the compound of formula (I) where Z represents NR” wherein R® represents (C,-Ce)alkyl group substituted with hydroxy group at a-position, Y! represents “=O group’, Y* and Y> independently represent hydrogen atom and all other symbols are as defined above, with a base.
40. A process for the preparation of compound of formula (I), v2 x 1 . ANd He 0 @ {id + ow where Z represents NR” wherein R® represents substituted or unsubstituted (Ci-Ce)alkyl or aralkyl, Y! represents =0 group’, Y? and Y? independently represent hydrogen atom; . R! represents halo, azido, isothiocyanate, thioalcohol, OR*, NHR? or N(RY, where R* represents hydrogen atom, or substituted or unsubstituted groups selected from acyl, thioacyl, (Ci-Ce)alkoxycarbonyl, (C3-Co)eycloalkoxythiocarbonyl, (Cs- Ce)alkenyloxycarbonyl, (C2-Ce)alkenylcarbonyl, aryloxycarbonyl, (C)- Cs)alkoxythiocarbonyl, (C2-Co)alkenyloxythiocarbonyl, aryloxythiocarbonyl, -C(=0)- C(=0)-akkyl, -C(=0)-C(=0)-aryl, -C(=0)-C(=0)-alkoxy, -C(=0)-C(=0)-aryloxy, - (C=S)-S-alkyl, -(C=S)-NH,, -(C=S)-NH-alkyl, -C(=S)-N-(alkyl),, -C(=S)-NH-alkenyl, (C=8)-(C=0)-alkoxy, -(C=8)-(C=0)-aryloxy, -C(=S)-0-(C=0)-alkyl, C(=S)-C(=S)- alkyl, -C(=8)-C(=S)-aryl, thiomorpholinylthiocarbony! or pyrrolidinylthiocarbonyl; R? and R® may be same or different and independently represent hydrogen, halogen atom, (Ci-Ce)alkyl group, halo(C,-Cg)alkyl, cyano, nitro, SR*, NR? OR? where R? represents substituted or unsubstituted (C;-Cg)alkyl group, or halo(C,-Cq)alkyl; Z represents S, O, =CH or NR" where R” represents hydrogen or substituted or unsubstituted (Ci-Ce)alkyl, (Cz2-Ce)alkenyl, (C,-Cg)cycloalkyl, (Ci-Colalkoxy, aryl, aralkyl, aryloxy, (Ci- Ce)alkylcarbonyl, arylcarbonyl, (Ci-Co)alkoxycarbonyl or aryloxycarbonyl its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: reacting the compound of formula (I) where Z represents NR” wherein R® represents hydrogen, Y' represents ‘=0’ group, Y? and Y? independently represent hydrogen atom and all other symbols are as defined above, with a base and alkyl halide.
41. The compound according to claim 1, wherein the substituents on R® are selected from hydroxy, halogen, nitro, amino, alkoxy, carboxy or cyano,
42. Pharmaceutically acceptable salt according to claim 7 wherein the salts of organic bases are selected from N,N’-diacetylethylenediamine, betaine, caffeine, 2- : diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, ~ glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N’- diphenylethylenediamine, N,N’-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine. :
43. Pharmaceutically acceptable salt according to claim 7 wherein the salts of chiral bases lare selected from alkylphenylamine, glycinol, phenyl glycinol. oo :
44. Pharmaceutically acceptable salt according to claim 7 wherein the salts of natural amino acids are selected from glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine.
45. Pharmaceutically acceptable salt according to claim 7 wherein the salts of unnatural amino acid, substituted amino acids are selected from D-isomers, guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl such as methyl, ethyl, propyl and the like; alkenyl such as cthenyl, propenyl, butenyl and the ~~ like; alkynyl such as ethynyl, propynyl.
46. Pharmaceutically acceptable salt according to claim 7 wherein the addition salts are selected fromsulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, - ketoglutarates. :
47. A'process for the preparation of compound of formula (I), Y2 il 1 . ANE Na 0 @ Yee + aN where R' represents halogen atom; R? and R> are same or different and independently represent hydrogen, halogen atom, (C,-Cs)alkyl group, halo(C-Cg)alkyl, cyano, nitro, SRY NR? OR*® where R* represents substituted or unsubstituted (Ci-Ce)alkyl group, or halo(C,-Ce)alkyl; Z represents S, O, =CH or NR® where R® represents hydrogen, or substituted or unsubstituted (Ci-Ce)alkyl, (C,-Cs)alkenyl, (Ci-Cg)cycloalkyl, (Ci- Ce)alkoxy, aryl, aralkyl, aryloxy, (C;-C¢)alkylcarbonyl, arylcarbonyl, (Ci- Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y* independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (C;-Cgalkyl, hydroxy(Ci-Ce)alkyl, (Ci-Ce)alkoxy(C;-Ce)alkyl, (C,-Cs)alkoxycarbonyl, carboxy(C;- Ce)alkyl, (Ci-Ce)alkylsulfonyl, (Cy-Ce)alkylcarbonylamino(C;-Cg)alkyl, arylcarbonylamino(Ci-Ce)alkyl, (Ci-Ce)alkylcarbonyloxy(C,-Cg)alkyl, amino(C;- Ce)alkyl, mono(C;-Cg)alkylamino, di(C,-Cg)alkylamino, arylamino, (C;-Ce)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl; Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms, its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates; which comprises: reacting a compound of formula (I) where R' represents hydroxy group and all other symbols are as defined above, with tetrahalomethane group in the presence of PPh; or P(alkyl)s. :
P
48. A process for the preparation of compound of formula D, g i ° . BN nd Paar oO yA y3 + {gt . where R! represents ‘SH’ group; R? and R® are same or different and independently represent hydrogen, halogen atom, (C;-Cs)alkyl group, halo(C;-Cs)alkyl, cyano, nitro, SR® NR? OR® where R® represents substituted or unsubstituted (C,-Cg)alkyl group, or halo(C,-Cg)alkyl; Z represents S, O, =CH or NR" where R® represents hydrogen, or substituted or unsubstituted (C;-Cg)alkyl, (Cx-Cy)alkenyl, (C,-Ce)cycloalkyl, (Ci- Ce)alkoxy, aryl, aralkyl, aryloxy, (C;-Cg)alkylcarbonyl, arylcarbonyl, (C;- Ce)alkoxycarbonyl or aryloxycarbonyl; Y' represents =O or =S group and Y? and Y? independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, =O, =S group, or substituted or unsubstituted groups selected from (Ci-Ce)alkyl, hydroxy(C,-Ce)alkyl, (C,-Cs)alkoxy(C;-Cg)alkyl, (Cy-Ce)alkoxycarbonyl, carboxy(C,- Celalkyl, (C1-Cg)alkylsulfonyl, (Ci-Co)alkylcarbonylamino(C;-Cs)alkyl, arylcarbonylamino(C,;-Cg)alkyl, (Ci-Ce)alkylcarbonyloxy(Ci-Ce)alkyl, amino(C;- Ce)alkyl, mono(C;-Cs)alkylamino, di(C,-Ce)alkylamino, arylamino, (C;-Cg)alkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl: Y? and Y? when present on adjacent carbon atoms together also form a substituted or unsubstituted 5 or 6 membered aromatic or non-aromatic cyclic structure, optionally containing one or two hetero atoms, its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its ‘pharmaceutically acceptable solvates; which comprises: (i) reacting the compound of formula (I) where R' represents ‘halogen atom, to produce a compound of formula (XX), : v2 i 2 : 2nd Hn 0 XX) yey +£ —{_scoc,
: 158 PCT/IN01/00227 where all symbols are as defined above, with a base and thioacetic acid, (11) reacting the compound of formula (XX), to produce a compound of formula (I) where R! represents SH’ group and all other symbols are as defined earlier, with base.
49. Use of a compound of formula (I) for treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 to a patient in need thereof.
50. Use of a compound for treating a bacterial infection comprising administering a pharmaceutical composition as claimed in claims 31 and 32 to a patient in need thereof.
51. Use of a compound of formula (I) for treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I) as claimed in claim 6 to a patient in need thereof.
52. Use of a compound for treating a bacterial infection comprising administering a pharmaceutical composition as claimed in claims 35 and 36 to a patient in need thereof.
53. A compound according to any one of claims 1, or 21, or 23, or 25, or 27, or 29, substantially as herein described and illustrated.
54. A process according to any one of claims 8 to 20, or 22, or 24, or 26, or 28, or 30, or 39, or 40, or 47, or 48, substantially as herein described and illustrated.
55. A composition according to claim 31, or claim 35, substantially as herein described and illustrated.
56. Use according to any one of claims 33, or 37, or 49 to 52, substantially as herein described and illustrated.
57. A substance or composition for use in a method of treatment according to claim 34, or claim 38, substantially as herein described and illustrated.
58. A new compound; a new process for preparing a compound; a new composition; a new use of a compound as claimed in claim 1; a new use of a compound as claimed in claim 6; or a substance or composition for a new use in a method of treatment; substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
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IN1124MA2000 | 2000-12-26 |
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ZA200304945B true ZA200304945B (en) | 2004-09-27 |
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ZA200304945A ZA200304945B (en) | 2000-12-26 | 2003-06-25 | Heterocyclic compounds having antibacterial activity, process for their preparation and pharmaceutical compositions containing them. |
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UA (1) | UA80090C2 (en) |
ZA (1) | ZA200304945B (en) |
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2001
- 2001-12-26 UA UA2003077041A patent/UA80090C2/en unknown
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