Field of the Invention
Provided herein are substituted aromatic compounds, which are tRNA synthetase
inhibitors, and hence can be used as antimicrobial agents. Compounds described herein can be
used for the treatment or prevention of a condition caused by or contributed to by gram positive,
gram negative, anaerobic bacteria or fungal organisms, more particularly against bacterium, for
example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia,
Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium,
Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and fungal organisms, for
example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton,
Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis,
Trichophyton, or Trichosporium. Processes for the preparation of these compounds,
pharmaceutical compositions thereof, and method of treating microbial infections are also
provided.
Background of the Invention
Antibiotics are of immense value for combating infectious diseases. In recent decades,
the effectiveness of antibiotics has been threatened by an inexorable rise in the prevalence of
microbial drug resistance. Some important pathogens have serious resistance problems.
Staphylococcus aureus is perhaps the most significant of these pathogens. It causes community
and hospital acquired infections and is associated with high morbidity and mortality rates.
Ancomycin has been used as the antibiotic of last resort to treat methicillin-resistance
Staphylococcus aureus infections (MRSA) with multiple resistance. Strains with some level of
resistance to vancomycin (Vancomycin-intermediates-resistant S. aureus, VISA) have been
known since 1996, but the newly identified highly resistant strain (VRSA) heralds a new stage
in the battle with this pathogen. Other serious treatment problems include multidrug resistance
in tuberculosis, vancomycin resistant enterococci (VRE), resistance owing to extended spectrum
p-lactamases (ESBLs) in Enterobacteriaceae and Pseudomonas aeruginosa, and penicillin
resistance in Streptococcus pneumoniae.
These circumstances have prompted efforts to develop new antibiotics that overcome the
emerging antibiotic resistance bacteria. The amino acyl tRNA synthetases are essential enzymes
found in all living organisms. These enzymes have emerged as an attractive target for the
development of new antibiotics. Amino acyl tRNA synthetases charge tRNA molecules with
their corresponding amino acid, an essential step in protein synthesis. There are 20 tRNA
synthetases, most of which correspond to attractive broad-spectrum antibacterial targets. This is
a validated target class in that pseudomonic acid A, also known as mupirocin, a natural product
from Pseudominas fluorescens, inhibits isoleucyl tRNA synthetase and is marketed as a topical
antibiotic Bactroban. Other known natural products directed against amino acyl tRNA
synthetases include borrelidin, furanomycin, granaticin, indolmycin, ochartoxin A, and
cispentacin, none of them has been developed as antibiotic compounds.
U.S. Patent Application Nos. 20040224981 and 20030013724 disclose tRNA synthetase
inhibitors. WO 00/18772 discloses condensed imidazolidinone as tRNA synthetase inhibitors.
U.S. Patent Nos. 5,191,093 and 4,916,155 disclose crystalline pseudomonate, process for its
production and its use in human and veterinary medicines. U.S. Patent No. 4,916,155 discloses
crystalline calcium pseudomonate or the hydrate thereof, and their use in human and veterinary
medicine.
Novel synthetic compounds, which target tRNA synthetases, offer clear advantages as
useful therapeutic agents to curb the threat of drug resistance.
Summary of the Invention
Accordingly, this invention provides substituted aromatic compounds, which are tRNA
synthetase inhibitors, and hence can be used for the treatment of microbial infections, and
processes for the synthesis of these compounds. Pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, stereoisomers, prodrugs, metabolites, polymorphs and Noxides
of these compounds having same type of activity are also provided. Pharmaceutical
compositions containing the described compounds (Formula I) together with one or more
pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment
of microbial infections. Other aspects will be set forth in the accompanying description which
follows and in part will be apparent from the description or may be learnt by the practice of the
invention.
In one aspect, there are provided compounds having the structure of Formula I,
Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Cy can be cyclohexyl or cyclopentyl;
X can be -CH2CH(CH3)-, -CH(F)CH(CH3)-, -CH(OH)CH(CH3> or -CH2CH(F)CH2-;
Y can be NH;
Z can be -CH2-;
Xi and X2 can be CH or N;
R can be NHC(NH)NH2, NHCOOCH2Ri or NHSO2R2;
RI can be 5-(2-thienyl)isoxazolyl;
R2 can be aryl, heteroaryl or heterocyclyl.
In a second aspect, there is provided a method for treating or preventing a subject
suffering from a condition caused by or contributed to by Gram positive, Gram negative,
anaerobic bacteria or fungal organisms, comprising administering to said subject, a
therapeutically effective amount of a compound or a pharmaceutical composition described
herein.
Bacterium, for example, Staphylococci, Enterococci, Streptococci, Haemophilus,
Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium,
Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae may
cause the bacterial infections.
Organisms, for example, Aspergillus, Blastomyces, Candida, Coccidiodes,
Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces,
Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium, Enterobactericeae may cause
the fungal infections.
The conditions may be, for example, community acquired pneumonia, upper and lower
respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or
bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection,
foreign body, prosthesis infections or peptic ulcer disease.
In a third aspect, there are provided processes for the preparation of compounds as
described herein.
The following definitions apply to terms as used herein:
The term "aryl" refers to substituted phenyl, wherein substituents are selected from -
OCH3; -F; -NH2; -OH; NHC(O)CH3; NHSO2CH3; NHC(O)OCH3; 5-oxo-l,5-dihydro-4H-1,2,4-
triazol-4-yl; 5-methyl-l,3,4-oxadiazol-2-yl; 1-methyl-lH-pyrazol-4-yl; 3,5-dimethylisoxazol-4-
yl; IH-pyrrol-l-yl; thiophene-3-sulfonamido; IH-tetrazol-l-yl; IH-pyrrol-l-yl; l,3-oxazol-5-yl;
lH-l,2,4-triazol-l-yl; lH-l,2,3-triazol-l-yl; 1-methyl-lH-imidazole-4-sulfonamido; 1,2,3-
thiadiazol-4-yl; 2-methyl-2H-tetrazol-5-yl; 5-methyl-l,3,4-oxadiazol-2-yl; 2-methyl-l,3-thiazol4-
yl; thiophene-2-sulfonamido; 2-oxo-l,3-oxazolidin-3-yl; l,2,4-oxadiazol-3-yl; IH-pyrazol-lyl
or [(alkyl or dialkylamino) sulfonyl]amino.
The term 'heteroaryl" refers to 5-bromo-l,3-thiazole-2-yl; 2-amino-pyrimidine-5-yl; 1-
benzofuran-2-yl; l-benzothiophene-2-yl; 5-methyl-lH-benzimidazole-2-yl; 5-fluoro-3-methyl-lbenzothiophene-
2-yl; 5-chloro-l,3-benzothiazole-2-yl; 2-amino-H-benzimidazole-5-yl; 2-aminol,
3-benzothiazole-4-yl; 2-amino-l,3-benzothiazole-6-yl; l,3-benzothiazol-2-acetamide-6-yl; 5-
chloro-2,1,3-benzoxadiazole-4-yl; 2,1,3-benzothiadiazole-5-yl; 2-(dimethylamino)-1,3-
benzothiazole-6-yl; l,3-benzothiazol-2-L-alaninamide-6-yl; optionally substituted thiophene
(wherein substituents are selected from 3,5-dimethylisoxazol-4-yl or isoxazol-5-yl); pyridine
substituted with lH-l,2,4-triazol-l-yl;lH-pyrrol-l-yl; 2-furyl; 3-furyl; IH-trtrazol-l-yl; 2-
thienyl; IH-imidazol-lyl; pyrrolidine-1-yl; morpholine-N-y; Br; NH2; NHC(NH)NH2 or
NHSO2RX (wherein Rx is methyl, 2-thiophenyl or N-methyl-imidazolyl).
The term 'heterocyclyl" refers to 2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-yl;
l,2,3,4-tetrahydroisoquinoline-7-yl; 1-(trifluoroacetyl) indoline-5-yl; indoline-5-yl; 4-oxo-3,4-
dihydroquinazoline-2-yl; 2-oxo-1,2-dihydroquinoline-6-yl; 1 -methyl-2-oxo-1,2-
dihydroquinoline-6-yl; l-ethyl-2-oxo-l,2-dihydroquinoline-6-yl or 2-oxo-2,3-dihydro-l,3-
benzoxazole-6-yl.
The term "pharmaceutically acceptable solvates" refers to solvates with either water
(e.g., hydrates, hemihydrate or sesquihydrate), or pharmaceutically acceptable solvents, for
example solvates with common organic solvents as ethanol and the like. Such solvates are also
encompassed within the scope of the disclosure.
The present invention also includes within its scope prodrugs of these agents. In general,
such prodrugs will be functional derivatives of these compounds, which are readily convertible
in vivo into the required compound. Conventional procedure for the selection and preparation of
suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H
Bundgaard and, Elsevier, 1985. As used herein the term "prodrugs" refers to the compounds
that are rapidly transformed in vivo to yield the parent compound of Formula I, for example by
hydrolysis in blood.
The described compounds may get metabolized in vivo and these metabolites are also
encompassed within the scope of this invention.
The term "polymorphs" includes all crystalline form as well as amorphous forms for
compounds described herein and as such are included in the present invention.
The compounds described herein can also be used in combination with one or more
aminoacyl tRNA synthetase (i.e mupirocin) inhibitors, antibacterial agents or mixture thereof.
Aminoacyl tRNA synthetase inhibitors and the antibacterial agents may be widely chosen from
among those known in the prior art or subsequently discovered and/or hereafter discovered
and/or hereafter developed.
The term "antibacterial agents" as used herein refers to agent, which destroys bacteria or
inhibits their growth, for example, pencillins, cephalosporins, aminoglycosides, tetracyclines,
macrolides, lincosamides, streptogramins, fluoroquinolones, polypeptides, rifampicin,
mupirocin, cycloserine, aminocyclitols, glycopeptides or oxazolidinones.
The phrase "pharmaceutically acceptable carriers" is intended to include non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any
type.
The term "pharmaceutically acceptable salts" refer to a salt prepared from
pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metal or organic base.
Examples of such metal salts include, but are not limited to, lithium, sodium, potassium,
calcium, magnesium, zinc, aluminum and the like. Examples of such organic bases include, but
are not limited to, amino acid, ammonia, mono-alkyl ammonium, dialkyl ammonium, trialkyl
ammonium and N-methyl glucamine and the like. The free acid forms of compounds of the
present invention may be prepared from the salt forms, if desired, by contacting the salt with
dilute aqueous solution of an acid, such as hydrochloric acid. The base addition salts may differ
from the free acid forms of the compounds of this invention in such physical characteristics as
solubility and melting point.
The term "pharmaceutically acceptable salts" can further refer to salts prepared from
pharmaceutically acceptable non-toxic inorganic or organic acids. Examples of such inorganic
acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric,
carbonic, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not
limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of
organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic,
methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-
hydroxyethanesulfonic acid and the like.
The compounds of present invention include stereoisomers. The term "stereoisomer"
refers to compounds, which have identical chemical composition, but differ with regard to
arrangement of the atoms and the groups in space. These include enantiomers, diastereomers,
geometrical isomers, atropisomer and conformational isomers as defined by the IUPAC 1974
Recommendations for Section E. All these stereoisomers are included within the scope of this
invention.
The term "subject" as used herein refers to human or lower mammal.
The term "treatment", as used herein, unless otherwise indicated, includes the treatment
or prevention of a bacterial or fungal infection as provided in the method of the present
invention.
The term "pharmaceutically acceptable" means approved by regulatory agency of the
federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized
pharmacopoeia for use in animals, and more particularly in humans.
Detailed Description of the Invention
The compounds described herein may be prepared by techniques well known in the art
and familiar to the average synthetic organic chemist. In addition, the compounds of the present
invention may be prepared by the following reaction sequences as depicted in Schemes I, la, Ib,
Ic, Id, II, Ha, lib, He, lid, III, IV, V, VI, VII, VIII and IX.
Scheme 1
(Figure Removed)
The sulfonamide of Formula 5 can be prepared according to Scheme I. Thus, reacting a
compound of Formula 2 with a compound of Formula 3 to give a compound of Formula 4,
which on oxidation gives sulfonamide of Formula 5 (wherein Xi, Xa and R2 are the same as
defined earlier).
The reaction of a compound of Formula 2 can be carried out in one or more organic
bases, for example, pyridine, triethylamine, trimethylamine, tributylamine or 4-Ndimethylaminopyridine
or mixtures thereof. The oxidation of a compound of Formula 4 can be
carried out in the presence of one or more oxidizing agents (e.g., Dess-Martin periodinane, 2-
iodoxybenzoic acid, N-chloro succinimide, pyridinium chlorochromate, Swern Oxidation
reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent
(dicyclohexylcarbodiimide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid,
aqueous sulfuric acid and acetone), pyridinium dichromate, l-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride) or mixtures thereof, in one or more solvents, for example,
chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or dichloroethane),
polar aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide, acetone, tetrahydrofuran or
acetonitrile) or mixtures thereof. N-Chlorosuccinamide can be used in combination with
dimethyl sulphide and l-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride can be
used in combination with dimethylsulfoxide..
Formula 6 Formula 7 Formula 8
The compound of Formula 8 can be prepared according to Scheme la. Thus, reacting a
compound of Formula 6 with a compound of Formula R4H to give a compound of Formula 7,
which on oxidation gives a compound of Formula 8 (wherein X\ and X: are the same as defined
earlier; R3 is H or R4, wherein R4 is substituent of phenyl).
The reaction of a compound of Formula 6 can be carried out in the presence of one or
more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydrogen
carbonate, sodium acetate or cesium carbonate in one or more polar aprotic solvents (e.g., Nmethyl-
2-pyrrolidinone, dimethlyformamide or dimethylsulfoxide) or mixtures thereof. The
oxidation of a compound of Formula 7 can be carried out using the procedures described in
Scheme I.
Scheme Ib
The compound of Formula 10 can be prepared according to Scheme Ib. Thus, reacting a
compound of Formula 9 with a compound of Formula RyB(OH)2 to give a compound of
Formula 9a, which on oxidation gives a compound of Formula 10 (wherein, Ry is H, 3,5-
dimethylisoxazol-4-yl or isoxazol-5-yl; Xi and Xa are the same as defined earlier).
8
The reaction of a compound of Formula 9 can be carried out in one or more polar protic
solvents (e.g., methanol, ethanol, propanol, isopropanol, t-butanol or water). The reaction of a
compound of Formula 9 can also be carried out in the presence of copper (I) iodide, palladium
catalyst, for example, palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II)
propionate, tetra kis (triphenylphosphine) palladium (0), tris (dibenzylidineacetone) palladium
(0) or bis (triphenylphosphine) palladium (II) chloride in one or more inorganic bases (e.g.,
potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate or cesium
carbonate). The oxidation of a compound of Formula 9a to give a compound of Formula 10 can
be carried out using the procedures described in Scheme I.
(Figure Removed)
The compound of Formula 15 can be prepared according to Scheme Ic. Thus, reacting a
compound of Formula 11 with imidazole to give a compound of Formula 12, which on treatment
with a compound of Formula R1CFH2OH [wherein RI is 5-(2-thienyl) isoxazolyl] gives a
compound of Formula 13 (wherein Rg is a protecting group, for example, tertiory
butoxycarbonyl, tert-butyldimethylsilyl, trimethylsilyl, 4-benzyloxybutyryl, 1,4-diazabicyclo
[2.2.1] octane or tert-butyldiphenylsilyl), which on deprotection gives a compound of Formula
14, which is finally oxidized to give a compound of Formula 15.
The reaction of a compound of Formula 11 can be carried out in the presence of one or
more coupling agents (e.g., N, N-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or l-(3-
dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride) in one or more solvents, for
example, chlorinated solvents (e.g., chloroform, dichloromethane, dichloroethane or
tetrachloromethane), polar aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide or
acetone) or in mixtures thereof. The reaction of a compound of Formula 12 can be carried out in
one or more solvents, for example, chlorinated solvent (e.g., dichloromethane, dichloroethane,
chloroform or tetrachloromethane), aprotic solvents (e.g., dimethylsulfoxide,
dimethylformamide or acetone) or in mixtures thereof. The deprotection of a compound of
Formula 13 can be carried out in the presence of tetra-n-butylammonium fluoride in one or more
solvents, for example, ethers (e.g., tetrahydrofuran, dioxane or ether), polar aprotic solvents
(e.g., dimethylsulfoxide, dimethylformamide or acetone) or in mixtures thereof. The oxidation
of a compound of Formula 14 can be carried out using the procedures described in Scheme I.
(Figure Removed)
The compound of Formula 19 can be prepared according to Scheme Id. Thus, reacting a
compound of Formula 16 with chlorosulfonic acid to give a compound of Formula 17, which on
treatment with a compound of Formula 2 gives a compound of Formula 18, which is finally
oxidized to give a compound of Formula 19.
The reaction of a compound of Formula 17 can be carried out in one or more organic
bases (e.g., pyridine, triethylamine, trimethylamine, tributylamine or 4-Ndimethylaminopyridine).
The oxidation of a compound of Formula 18 can be carried out out in
the presence of one or more oxidizing agents (e.g., Dess-Martin periodinane, 2-iodoxybenzoic
acid, N-chloro succinimide, pyridinium chlorochromate, Swern Oxidation reagent (oxalyl
chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodiimide
and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and
acetone), pyridinium dichromate or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride) or mixtures thereof, in one or more solvents, for example, chlorinated solvents
(e.g., chloroform, dichloromethane, carbon tetrachloride or dichloroethane), polar aprotic
solvents (e.g., dimethylsulfoxide, dimethylformamide, acetone, tetrahydrofuran or acetonitrile)
or in mixtures thereof. N-Chlorosuccinamide can be used in combination with dimethyl sulphide
and l-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride can be used in combination
with dimethylsulfoxide.
(Figure Removed)
The compound of Formula 25 can be prepared according to Scheme II. Thus, reacting a
compound of Formula 20 with a compound of Formula 21 to give a compound of Formula 22,
which on treatment with tosyl chloride gives a compound of Formula 23, which on reaction with
a compound of Formula Cy-Ha gives a compound of Formula 24 (wherein Ha is F, Cl, Br or I),
which is finally deprotected to give a compound of Formula 25 (wherein Cy is the same as
defined earlier).
The reaction of a compound of Formula 20 can be carried out in one or more solvents,
for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or
dichloroethane), polar aprotic solvent (e.g., dimethylsulfoxide, dimethylformamide or acetone)
or in mixtures thereof. The reaction of a compound of Formula 22 can be carried out in one or
more solvents, for example, ethers (e.g., ether, dioxane, or tetrahydrofuran), chlorinated solvents
(e.g., dichloromethane, dichloroethane, trtrachloromethane or chloroform) or in mixtures
thereof. The reaction of a compound of Formula 22 can also be carried out in alkali or alkaline
metal hydroxide, for example, potassium hydroxide, sodium hydroxide, calcium hydroxide or in
mixtures thereof. The reaction of a compound of Formula 23 can be carried out in the presence
of magnesium (in dry ether) in one or more solvents, for example, ethers (e.g., ether, dioxane or
tetrahydrofuran), chlorinated solvents (e.g., dichloromethane, dichloroethane,
tetrachloromethane or chloroform) or mixture thereof. The deprotection of a compound of
Formula 24 can be carried out in the presence of one or more arganic acids (e.g., trifluoro acetic
acid or paratoluene sulfonicacid), mineral acids (e.g., hydrochloric, hydrobromic or hydroiodic
acid) in one or more solvents, nitriles (e.g., acetonitrile or propionitrile), polar protic solvents
(e.g., water, methanol, ethanol, propanol, isopropanol or tert-butanol) or mixtures thereof.
(Figure Removed)
The compound of Formula 27 (Formula 25, wherein Cy is cyclohexyl) can also be
prepared according to Scheme Ha. Thus, a compound of Formula 26 can be reduced to give a
compound of Formula 27.
The reduction of a compound of Formula 26 can be carried out in one or more reducing
agents (e.g., platinum oxide, palladium hydroxide or Raney nickel) in the presence of one or
more organic acids (e.g., acetic or trifluoroacetic acid) or mixtures thereof.
Scheme lib
OH
CH3 CH3 CH3 LH3
Formula 28 Formula 29 Formula 30 Formula 31
The compound of Formula 31 can be prepared according to Scheme lib. Thus, reacting a
compound of Formula 28 with benzylbromide to give a compound of Formula 29, which on
fluorination gives a compound of Formula 30, which is finally deprotected to give a compound
of Formula 31.
The reaction of a compound of Formula 28 can be carried out in one or more solvents,
for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or
dichloroethane), polar aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide or acetone)
or mixtures thereof. The reaction of a compound of Formula 29 with (Diethylamino) sulfur
trifluoride (DAST) can be carried out in one or more solvents, for example, chlorinated solvents
(e.g., dichloromethane, dichloroethane or chloroform), ethers (e.g., ether, dioxane, or
tetrahydrofuran) or in mixtures thereof. The deprotection of a compound of Formula 30 can be
carried out in the presence of reducing agents (e.g., pallidium hydroxide or raney nickel) or one
or more mineral acids (e.g., hydrochloric, hydrobromic or hydroiodic acid) in one or more
solvents, for example, a polar protic solvents (e.g., water, methanol, ethanol, propanol,
isopropanol or tert-butanol) or mixtures thereof.
Scheme He
Formula 32 Formula 33 Formula 34 Formula 35
The compound of Formula 35 can be prepared according to Scheme He. Thus, reacting a
compound of Formula 32 with a compound of benzyl bromide gives a compound of Formula 33,
which on fluorination gives a compound of Formula 34, which is finally deprotected to give a
compound ofFormula35.
The reaction of a compound of Formula 32 can be carried out in one or more solvents,
for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or
dichloroethane), polar aprotic solvents (e.g., dimethylsulfoxide, dimethylformamide or acetone)
or mixtures thereof. The reaction of a compound of Formula 33 with (Diethylamino) sulfur
trifluoride (DAST) can be carried out in one or more solvents, for example, chlorinated solvents
(e.g., dichloromethane, dichloroethane, carbon tetrachloride or chloroform), ethers (e.g., ether,
dioxane, or tetrahydrofuran) or mixtures thereof. The deprotection of a compound of Formula 34
can be carried out in the presence of reducing agents (e.g., palladium hydroxide or Raney nickel)
or one or more mineral acids (e.g., hydrochloric, hydrobromic or hydroiodic acid) in one or
more solvents, for example, nitriles (e.g., acetonitrile or propionitrile), chlorinated solvents (e.g.,
dichloromethane, dichloroethane, carbon tetrachloride or chloroform), polar protic solvents (e.g.,
water, methanol, ethanol, propanol, isopropanol or tert-butanol) or mixture thereof.
(Figure Removed)
The compound of Formula 35b can be prepared according to Scheme lid. Thus, reducing
the compound of Formula 35a to give a compound of Formula 35b.
The reduction of a compound of Formula 35a to give a compound of Formula 35b can be
carried out in one or more reducing agents (e.g., platinum oxide, palladium hydroxide or Raney
nickel) in the presence of one or more organic acids (e.g., acetic acid or trifluoroacetic acid) or
mixtures thereof.
(Figure Removed)
The compound of Formula 37 can be prepared according to Scheme III. Thus, reacting a
compound of Formula 5 with a compound of Formula 36 [wherein Formula 36 is formula 25,
27, 31, 35 or 35b] to give a compound of Formula 37 (wherein, Xj, X2 and R2 are the same as
defined earlier).
The reaction of a compound of Formula 5 with can be carried out in the presence of one
or more reducing agents (e.g., sodium cyanoborohydride, sodium borohydride or
sodiumtriacetoxyborohydride) in one or more solvents, nitriles (e.g., aceto nitrile or
propionitrile), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol or tertbutanol)
or mixture thereof.
(Figure Removed)
The compound of Formula 38 can be carried out in the presence of one or more reducing
agents (e.g., sodium cyanoborohydride, sodium borohydride or sodiumtriacetoxyborohydride) in
one or more solvents, nitriles (e.g., aceto nitrile or propionitrile), polar protic solvents (e.g.,
water, methanol, ethanol, propanol, isopropanol or tert-butanol) or mixture thereof.
(Figure Removed)
The compound of Formula 43 can be prepared according to Scheme V. Thus, protecting
a compound of Formula 39 with a protecting agent RsHal (wherein, Hal is F, CL, Br or I; RS is
tetrtiory butoxycarbonyl, tert-butyldimethylsilyl, trimethylsilyl, di-tert-Butyl dicarbonate, 4-
benzyloxybutyryl, 1,4-diazabicyclo [2.2.1] octane or tert-butyldiphenylsilyl) to give a compound
of Formula 40, which on reduction gives a compound of Formula 41, which on reaction with a
compounds of Formula 41 a or 41b to give a compound of Formula 42 or 42a, which on
deprotection gives a compound of Formula 43 or 43a.
The protection of a compound of Formula 39 can be carried out in the presence of one or
more organic bases (e.g., triethylamine, trimethylamine, pyridine or tert-butylamine) in one or
more chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform or
tetrachloromethane). The reduction of a compound of Formula 40 can be carried out in the
presence of a reducing agents (e.g., Raney Nickel in hydrazine hydrate, zinc, tin or iron) in the
presence of hydrochloric acid or lithium aluminium hydride. The reaction of a compound of
Formula 41 can be carried out in the presence of one or more coupling agents (e.g., N, Ncarbonyldiimidazole,
N, N-dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethyl
carbodiimide hydrochloride) in one or more solvents, for example, nitriles (e.g., acetonitrile or
propionitrile), chlorinated solvents (e.g., chloroform, dichloromethane, dichloroethane or
tetrachloromethane), polar aprotic solvents (e.g., dimethyl sulfoxide, dimethylformamide or
acetone) or mixtures thereof. The deprotection of a compound of Formula 42 or 42a can be
carried out in the presence of one or more mineral acids (e.g., hydrochloric, hydrobromic or
hydroiodic acid), organic acids (e.g., trifluoro acetic acid or paratoluene sulfonic acid) in one or
more polar protic solvents (e.g., water, methanol, ethanol, propanol or isopropanol).
Scheme VI
(Figure Removed)
The compound of Formula 46 can be prepared according to Scheme VI. Thus, reacting a
compound of Formula 44 with a compound of Formula RXSO2C1 to give a compound of Formula
45, which on deprotection gives a compound of Formula 46 (wherein Rx is methyl, dimethyl
amino, 2-thiophenyl or N-methyl-imidazolyl).
The reaction of a compound of Formula 44 can be carried out in the presence of one or
more organic bases (e.g., pyridine, triethylamine or trimethylamine). The deprotection of a
compound of Formula 45 can be carried out in the presence of one or more mineral acids (e.g.,
hydrochloric, hydrobromic or hydroiodicacid), organic acids (e.g., trifluoro acetic acid or
paratoluene sulfonic acid) in one or more solvents, for example, nitriles (e.g., acetonitrile or
propio nitrile), polar protic solvents (e.g., water, methanol, ethanol, propanol or isopropanol) or
mixtures thereof.
Scheme VII
(Figure Removed)
The compounds of Formula 49 can be prepared according to Scheme VII. Thus,
deprotecting a compound of Formula 40 with thiophenol or thioglycolic acid to give a
compound of Formula 47, which on reaction with a compound of Formula 47a gives a
compound of Formula 48, which on deprotection gives a compound of Formula 49.
The deprotection of a compound of Formula 40 can be carried out in the presence of one
or more inorganic bases (e.g., cesium carbonate, sodium carbonate, sodium hydrogen carbonate,
potassium carbonate or calcium carbonate) in one or more solvents, for example, nitriles (e.g.,
acetonitrile orpropionitrile), acetates (e.g., ethyl acetate or prppyl acetate), polar aprotic solvents
(e.g., acetone, dimethylsulfoxide or dimethylformamide) or mixtures thereof. The reaction of a
compound of Formula 47 can be carried out in the presence of one or more organic bases (e.g.,
pyridine, triethylamine or trimethylamine). The deprotection of compound of Formula 48 can be
carried out in the presence of one or more organic acids (e.g., trifluoro acetic acid or paratoluene
sulfonic acid), mineral acids (e.g., hydrochloric, hydrobromic or hydroiodic acid) in one or more
solvents, for example, nitriles (e.g., acetonitrile or propio nitrile), polar protic solvents (e.g.,
water, methanol, ethanol, propanol, isopropanol or butanol) or mixtures thereof.
(Figure Removed)
The compound of Formula 51 can be prepared according to Scheme VIII. Thus, reacting
a compound of Formula 47 with a compound of Formula 41 a to give a compound of
Formula 50, which on deprotection gives a compound of Formula 51.
The reaction of a compound of Formula 47 can be carried out in the presence of one or
more solvents, for example, nitriles (e.g, acetonitrile or propionitrile), chlorinated solvents (e.g.,
chloroform, dichloromethane, dichloroethane or tetrachloromethane), polar aprotic solvents
(e.g., dimethyl sulfoxide, dimethylformamide or acetone) or mixtures thereof. The deprotection
of a compound of Formula 50 can be carried out in the presence of one or more organic acids
(e.g., trifluoro acetic acid or paratoluene sulfonic acid), mineral acids (e.g., hydrochloric,
hydrobromic or hydroiodic acid) in one or more solvents, for example, nitriles (e.g, acetonitrile
or propionitrile), polar protic solvents (e.g., water, methanol, ethanol, propanol or isopropanol)
or mixtures thereof.
(Figure Removed)
The compound of Formula 56 can be prepared according to Scheme IX. Thus, reacting a
compound of Formula 52 with phenyl chloroformate to give a compound of Formula 53, which
on reaction with hydrazine hydrate gives a compound of Formula 54, which on cyclisation gives
a compound of Formula 55, which is finally deprotected to give a compound of Formula 56.
The reaction of a compound of Formula 52 can be carried out in one or more solvents,
for example, nitriles (e.g, acetonitrile or propionitrile), chlorinated solvents (e.g., chloroform,
dichloromethane, dichloroethane or tetrachloromethane), polar aprotic solvents (e.g.,
dimethylsulfoxide, dimethylformamide or acetone) or mixtures thereof. The reaction of a
compound of Formula 53 can be carried out in the presence of one or more coupling agents (e.g.,
1,4-dioxane, N, N-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or l-(3-
dimethylaminopropyi)-3 -ethyl carbodiimide hydrochloride) in one or more solvents, for
example, nitriles (e.g, acetonitrile or propionitrile), chlorinated solvents (e.g., chloroform,
dichloromethane, dichloroethane or tetrachloromethane), polar aprotic solvents (e.g.,
dimethylsulfoxide, dimethylformamide or acetone) or mixtures thereof. The reaction of a
compound of Formula 54 with formamidine acetate can be carried out in the presence of acids,
for example, acetic acid hydrochloride in one or more solvents, for example, nitriles (e.g,
acetonitrile or propionitrile), chlorinated solvents (e.g., chloroform, dichloromethane,
dichloroethane or tetrachloromethane), polar aprotic solvents (e.g., dimethylsulfoxide,
dimethylformamide or acetone) or mixtures thereof. The deprotection of a compound of
Formula 55 can be carried out in the presence of one or more organic acids (e.g., trifluoroacetic
acid or paratoluene sulfonic acid), mineral acids (e.g., hydrochloric, hydrobromic or hydroiodic
acid) in one or more solvents, for example, nitriles (e.g, acetonitrile or propionitrile), polar protic
solvents (e.g., water, methanol, ethanol, propanol or isopropanol) or mixtures thereof.
In the above schemes, where the specific bases, oxidizing agents, reducing agents,
coupling agents, solvents, etc., are mentioned, it is to be understood that other bases, oxidizing
agents, reducing agents, coupling agents, solvents, etc., known to those skilled in the art may be
used. Similarly, the reaction temperature and duration may be adjusted according to the desired
needs.
The compounds described herein possess antimicrobial activity against gram-positive,
gram-negative, anaerobic bacteria and fungal infections; They are useful as antimicrobial agents
for the treatment of infections diseases in human and animal.
Compounds of the present invention useful for such purpose are listed below:
A^-[2-({[(15)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-benzofuran-2-sulfonamide
(compound No. 1),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l-benzofuran-2-sulfonamide
(compound No.2),
N-[3-({[2-cyclohexyl-l-methylethyl]amino}methyl)pyridin-4-yl]thiophene-2-sulfonamide
(compound No.3),
2-amino-N-[2-( {[2-cyclohexyl-1 -methyl ethyl] amino} methyl)phenyl]-1 H-benzimidazole-,5-
sulfonamide (compound No.4),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]guanidine (compound No.5),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-(5 -oxo-1,5-dihydro-4H-1,2,4-
triazol-4-yl)benzenesulfonamide (compound No.6),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(5-methyl-l,3,4-oxadiazol-2-
yl)benzenesulfonamide (compound No.7),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(l-methyl-lH-pyrazol-4-
yl)benzenesulfonamide (compound No.8),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(3,5-dimethylisoxazol-4-
yl)benzenesulfonamide (compound No.9),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-dimethylisoxazol-4-
yl)thiophene-2-sulfonamide (compound No. 10),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-dimethylisoxazol-4-
yl)thiophene-2-sulfonamide (compound No. 11),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3-
[(methylsulfonyl)amino]benzenesulfonamide (compound No. 12),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-
{[(dimethylamino)sulfonyl]amino}benzenesulfonamide (compound No. 13),
N- [3 -({[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-4-yl] -1 -benzothiophene-2-
sulfonamide (compound No. 14),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -5- {[(1 -methyl-1 H-imidazol-4-
yl)sulfonyl]amino}pyridine-2-sulfonamide (compound No. 15),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-[(methylsulfonyl)amino]pyridine-
2-sulfonamide (compound No. 16),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -5 - [(2-
thienylsulfonyl)amino]pyridine-2-sulfonamide (compound No. 17),
5 -bromo-N- [2-( {[2-cyclohexyl-1 -methylethyl]amino} methyl)phenyl] -1,3 -thiazole-2-
sulfonamide (compound No. 18),
[5-(2-thienyl)isoxazol-3-yl]methyl [2-({[(lS)-2-cyclopentyl-lmethylethyl]
amino}methyl)phenyl]carbamate (compound No. 19),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -2-fluoro-5-( 1 H-pyrrol-1
yl)benzenesulfonamide (compound No.20),
2-amino-N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,3 -benzothiazole-4-
sulfonamide (compound No.21),
N- [2-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl]
amino}sulfonyl)phenyl]thiophene-3-sulfonamide (compound No.22),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -3-fluoro-4-( 1 H-tetrazol-1 -
yl)benzenesulfonamide (compound No.23),
N- [2-( {[(2S)-2-cyclohexyl-2-hydroxy-1 -methylethyl]amino} methyl)phenyl] -4-( 1 H-pyrrol-1 -
yl)benzenesulfonamide (compound No.24),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(l,3-oxazol-5-
yl)benzenesulfonamide (compound No.25),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -6-( 1H-1,2,4-triazol-1 -
yl)pyridine-3-sulfonamide (compound No.26),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )pyridin-3 -yl] thiophene-2-sulfonamide
(compound No. 2 7),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino } methyl)phenyl] -3 -fluoro-4-( 1 H-1,2,4-triazol-
1 -yl)benzenesulfonamide (compound No.28),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-( 1H-1,2,4-triazol-1 -yl)pyridine-3-
sulfonamide (compound No.29),
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-3-fluoro-4-( 1 H-tetrazol-1 -
yl)benzenesulfonamide (compound No.30),
N- [2-( {[2-cyclohexyl-1 -methylethyl]amino} methyl )phenyl] -6-( 1 H-pyrrol-1 -yl)pyridine-3-
sulfonamide (compound No.31),
N- [2-( {[2-cyclohexyl-1 -methylethyljamino} methyl)pyridin-3 -yl] -3 -fluoro-4-( 1 H-1,2,4-triazoll-
yl)benzenesulfonamide (compound No.32),
N-[2-({[2- methylethyl]amino}methyl)phenyl]thiophene-2-sulfonamide (compound
No.33),cyclohexyl-2-fluoro-l-
N- [2-( {[(1 S)-2-cyclopentyl -1 -methylethyl]amino} methyl)phenyl] -6-( 1 H-pyrrol-1 -yl)pyridine-3-
sulfonamide (compound No.34),
N- [3 -({[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-4-yl] -5-isoxazol-5 -ylthiophene-2-
sulfonamide hydrochloride (compound No.35),
2-amino-N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1,3 -benzothiazole-6-
sulfonamide (compound No.36),
2-amino-N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyljamino} methyl)phenyl]-1 H-benzimidazole-
6-sulfonamide (compound No.37),
5 - {[amino(imino)methyl] amino} -N- [2-( {[2-cyclohexyl-1 -
methylethyl]amino}methyl)phenyl]pyridine-2-sulfonamide (compound No.38),
N-[4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
methoxyphenyl]-!-methyl-lH-imidazole-4-sulfonamide (compound No.39),
N- [6-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-1,3-
benzothiazol-2-yl]acetamide (compound No.40),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -5-methyl-1 H-benzimidazole-2-
sulfonamide (compound No.41),
4-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-
fluorobenzenesulfonamide (compound No.42),
4-amino-N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -2-
methoxybenzenesulfonamide (compound No.43),
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl]amino} sulfonyl)-3 -
methoxyphenyl]acetamide (compound No.44),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -2-methoxy-4-
[(methylsulfonyl)amino]benzenesulfonamide (compound No.45),
methyl [4-({[2-( {[2-cyclohexyl-1 -
methyl ethyl] amino} methyl )phenyl] amino} sulfonyl)phenyl] carbamate (compound No.46),
N-[2-({ [(1 S)-2-cyclopentyl-l -methylethyl]amino}methyl)phenyl]-4-( 1,2,3-thiadiazol-4-
yl)benzenesulfonamide (compound No.47),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -4-(2-methyl-2H-tetrazol-5 -
yl)benzenesulfonamide (compound No.48),
N-[2-({ [(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-4-(2-methyl-2H-tetrazol-5-
yl)benzenesulfonamide (compound No.49),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(5-methyl-l,3,4-oxadiazol-
2-yl)benzenesulfonamide (compound No.50),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-furyl)pyridine-3-sulfonamide
(compound No. 51),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(2-furyl)pyridine-3-
sulfonamide (compound No.52),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-(3-furyl)pyridine-3 -sulfonamide
(compound No.53),
N-[2-({ [(1 S)-2-cyclopentyl-l -methylethyl] amino }methyl)phenyl]-6-(3-furyl)pyridine-3-
sulfonamide (compound No.54),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -1 -methyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide (compound No.55),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1 -methyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide (compound No.56),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino }methyl)phenyl] -6-( 1 H-tetrazol-1 -yl)pyridine-3-
sulfonamide (compound No.57),
N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino }methyl)phenyl]-6-(l H-tetrazol-1 -yl)pyridine-
3-sulfonamide (compound No.58),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-(2-thienyl)pyridine-3-
sulfonamide (compound No.59),
N-[2-({ [(1 S)-2-cyclopentyl-1 -methylemyl]amino}methyl)phenyl]-6-(2-thienyl)pyridine-3-
sulfonamide (compound No.60),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-imidazol-l-yl)pyridine-3-
sulfonamide (compound No.61),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-imidazol-lyl)
pyridine-3-sulfonamide (compound No.62),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-methyl-l,3-thiazol-4-
yl)benzenesulfonamide (compound No.63),
N-[2-({ [(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-3-(2-methyl-l ,3-thiazol-4-
yl)benzenesulfonamide (compound No.64),
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-5-fluoro-3-methyl-1 -
benzothiophene-2-sulfonamide (compound No.65),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-5-fluoro-3-methyl-lbenzothiophene-
2-sulfonamide (compound No.66),
N- [2-( {[2-cyclohexyl-2-fluoro-1 -methylethyl]amino} methyl)phenyl] -2-(trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide (compound No.67),
N-[4-( {[2-( {[2-cyclohexyl-2-fluoro-1 -
methylethyl]amino}methyl)phenyl]amino}sulfonyl)phenyl]thiophene-2-sulfonamide (compound
No.68),
N- [2-( {[2-cyclohexyl-2-fluoro-1 -methyl ethyl]amino} methyl)phenyl] -4-( 1 H-pyrrol-1 -
yl)benzenesulfonamide (compound No.69),
N-(2-{[(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)-2-(trifluoroacetyl)-l,2,3,4-
tetrahydroisoquinoline-7-sulfonamide (compound No.70),
N-(4-{[(2-{[(3-cyclohexyl-2-
fluoropropyl)amino] methyl} phenyl)amino] sulfonyl} phenyl)thiophene-2-sulfonamide
(compound No.71),
5-amino-N-[2-({ [2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-2-sulfonamide
(compound No.72),
5-chloro-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-2,l,3-
benzoxadiazole-4-sulfonamide (compound No.73),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1 -benzothiophene-2-
carboxamide (compound No.74),
N-(2-{[(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)thiophene-2-sulfonamide
(compound No.75),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -2,1,3-benzothiadiazole-5-
sulfonamide (compound No.76),
N-[4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
methoxyphenyl]thiophene-2-sulfonamide (compound No.77),
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl]amino} sulfonyl)-3 -
hydroxyphenyl]thiophene-2-sulfonamide (compound No.78),
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
hydroxyphenyljacetamide (compound No.79),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3-fluoro-4-(2-oxo-1,3 -oxazolidin-3-
yl)benzenesulfonamide (compound No.80),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(2-oxo-l,3-
oxazolidin-3-yl)benzenesulfonamide (compound No.81),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-l,2,3-triazol-lyl)
benzenesulfonamide (compound No.82),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-l,2,3-triazol-
1-yl)benzenesulfonamide (compound No.83),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-(trifluoroacetyl)indoline-5-
sulfonamide (compound No.84),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]indoline-5-sulfonamide (compound
No.85),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-( 1,2,4-oxadiazol-3 -
yl)benzenesulfonamide (compound No.86),
N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl]-4-( 1,2,4-oxadiazol-3-
yl)benzenesulfonamide (compound No.87),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3,4-
difluorobenzenesulfonamide (compound No.88),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-3 -yl] -4-(5-methyl-1,3,4-oxadiazol-
2-yl)benzenesulfonamide (compound No.89),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(lH-l,2,3-triazol-lyl)
benzenesulfonamide (compound No.90),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1 H-pyrazol-1 -
yl)benzenesulfonamide (compound No.91),
N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1 H-pyrazol-1 -
yl)benzenesulfonamide (compound No.92),
N-[2-({ [2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl]-6-pyrrolidin-1 -ylpyridine-3-
sulfonamide (compound No.93),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-pyrrolidin-l-ylpyridine-3-
sulfonamide (compound No.94),
N- [2-( {[2-cyc lohexyl-1 -methylethyl] amino} methyl)phenyl] -6-morpholin-4-ylpyridine-3-
sulfonamide (compound No.95),
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -6-morpholin-4-ylpyridine-3-
sulfonamid'e (compound No.96),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl]-1 -ethyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide (compound No.97),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l-ethyl-2-oxo-l,2-
dihydroquinoline-6-sulfonamide (compound No.98),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-l,2-dihydroquinoline-
6-sulfonamide (compound No.99),
6-bromo-A-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-3-sulfonamide
(compound No. 100),
2-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyrimidine-5-sulfonamide
(compound No. 101),
6-amino-N-[2-({ [2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-3-sulfonamide
(compound No. 102),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-2,3-dihydro-l,3-
benzoxazole-6-sulfonamide (compound No. 103),
5-chloro-N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,3 -benzothiazole-2-
sulfonamide (compound No. 104),
5-chloro-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l,3-benzothiazole-2-
sulfonamide (compound No. 105),
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -2-(dimethylamino)-1,3-
benzothiazole-6-sulfonamide (compound No. 106),
N-[6-({[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]amino}sulfonyl)-l,3-
benzothiazol-2-yl]-L-alaninamide (compound No. 107),
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-oxo-3,4-dihydroquinazoline-2-
sulfonamide (compound No. 108),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-(trifluoroacetyl)-l,2,3,4-
tetrahydroisoquinoline-7-sulfonamide (compound No. 109),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l,2,3,4-tetrahydroisoquinoline-7-
sulfonamide (compound No. 110),
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-l,2-dihydroquinoline-6-
sulfonamide (compound No.l 11),
N-[2-( {[2-cyclohexyl-1-methylethyl] amino }methyl)phenyl]-3-fluoro-4-(l H-imidazol-1-
yl)benzenesulfonamide (compound No.l 12),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methyl ethyl] amino} methyl)phenyl] -5 -fluoro-3-methyl-1 -
benzothiophene-2-sulfonamide (compound No.l 13),
N-[2-( {[(1 S)-2-cyclohexyl-1 -methylethyljamino }methyl)phenyl]-1 -methyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide (compound No.l 14),
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-ethyl-2-oxo-l,2-
dihydroquinoline-6-sulfonamide (compound No. 115),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-(2 -thienyl)pyridine-3 -
sulfonamide (compound No.l 16),
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-furyl)pyridine-3-
sulfonamide (compound No.l 17),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-( 1 H-tetrazol-1 -yl)pyridine-
3-sulfonamide (compound No.l 18),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-pyrrolidin-1 -ylpyridine-3 -
sulfonamide (compound No. 119),
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-methyl-l,3-thiazol-4-
yl)benzenesulfonamide (compound No. 120),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyljamino} methyl)phenyl] -5 -(3,5 -dimethylisoxazol-4-
yl)thiophene-2-sulfonamide (compound No. 121),
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-(5 -methyl-1,3,4-oxadiazol-
2-yl)benzenesulfonamide (compound No. 122),
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(l,2,4-oxadiazol-3-
yl)benzenesulfonamide (compound No. 123),
N-[2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1 H-pyrazol-1 -
yl)benzenesulfonamide (compound No. 124),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof.
Because of their antimicrobial activity, the compounds described herein may be
administered to an animal for treatment orally, topically, rectally, internasally or by a parenteral
route. The pharmaceutical compositions of the present invention comprise a pharmaceutically
effective amount of compounds described herein formulated together with one or more
pharmaceutically acceptable carriers.
Solid form preparations for oral administration include capsules, tablets, pills, powders,
granules, cachets and suppositories. For solid form preparations, the active compound can be
mixed with at least one inert, pharmaceutically acceptable excipients or carrier, for example,
sodium citrate, dicalcium phosphate and/or a filler or extenders, for example, starches, lactose,
sucrose, glucose, mannitol and silicic acid; binders, for example, carboxymethylcellulose,
alginates, gelatins, polyvinylpyrrolidinone, sucrose, or acacia; disintegrating agents, for
example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium
carbonate; absorption acceletors, for example, quaternary ammonium compounds; wetting
agents, for example, cetyl alcohol, or glycerol mono stearate; adsorbants, for example, Kaolin;
lubricants , for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol,
sodium luaryl sulphate and mixture thereof. In the case of capsules, tablets, or pills, the dosage
form may also comprise buffering agents.
The solid preparation of tablets, capsules, pills and granules can be prepared with coating
and shells, for example, enteric coating and other coatings well known in the pharmaceutical
formulating art.
Liquid form preparations for oral administration can include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs. For liquid form preparations, the active
compound can be mixed with water or other solvent, solubilizing agents and emulsifiers, for
example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example,
cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, and fatty acid esters of
sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include
adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening
agents, flavouring agents and perfuming agents.
Injectible preparations, for example, sterile injections, aqueous suspensions may be
formulated according to the art using suitable dispersing or wetting and suspending agent.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution
and isotonic sodium chloride.
Dosage forms for tropical or transdermal administration of compounds provided herein
include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
The active compound can be admixed under sterile condition with a pharmaceutically acceptable
carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations,
eardrops, eye ointments, powder and solution are also contemplated as being within the scope of
this invention.
The pharmaceutical preparation can be provided in a unit dosage form. In such forms,
the preparation is subdivided into unit doses containing appropriate quantities of the active
component. The unit dosage form can be packaged preparation, the package containing discrete
capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself
or it can be the appropriate number of any of these packaged forms.
Examples set forth below demonstrate general synthetic procedures for the preparation of
representative compounds. The examples are provided to illustrate particular aspect of the
disclosure and do not constrain the scope of the present invention as defined by the claims.
EXAMPLES
General Procedures
Example 1: Preparation of a compound of Formula 4
To a solution of a compound of Formula 2 (1.2 equiv.) in pyridine, a compound of
Formula 3 (1.0 equiv.) was added portion wise at about 0-5 °C. The reaction mixture was
allowed to come at an ambient temperature and stirred overnight. The solvent was evaporated
under reduced pressure. Water was added to the residue, which was then extracted with ethyl
acetate. The organic layer was washed with water, brine and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and the residue was purified by
column chromatography to yield the required product.
Example 2: Preparation of compound of Formula 5
To a solution of compound of Formula 4 (1.0 equiv.) in dichloromethane (20-30 mL)
was added Dess Martin Periodinane (1.5 equiv.). The reaction mixture was stirred overnight at
an ambient temperature, filtered and the mother liquor was washed with aqueous sodium
bicarbonate solution. The organic layer was dried and evaporated under reduced pressure. The
residue was purified by column chromatography to give the desired product.
Example 3: Preparation of a compound of Formula 9a
To a solution of a compound of Formula 9 (10.0 equiv., prepared according to Scheme I)
in propanol (15 mL) was added a compound of Formula RyB(OH)2 (12.0 equiv.). The reaction
mixture was degassed with argon for about 15 minutes. Tetrakis (triphenylphosphine)
palladium (0) (1.0 equiv.) was added to the reaction mixture. Sodium carbonate
(10.0 equiv.) in water was added to the reaction mixture. The reaction mixture was heated to
about 100 °C and stirred for about 5 hours in dark under argon atmosphere. The reaction
mixture was filtered, the residue was concentrated and the product was purified by column
chromatography.
Example 4: Preparation of a compound of Formula 10
The compound of Formula 10 was prepared using the procedure described for compound
of Formula 5.
Example 5: Preparation of compound of Formula 13
Compound of Formula 11 (1.0 equiv.) was taken in dry dichloromethane (5-10 mL) and
imidazole (1.5 equiv.) and N, N'-carbonyldiimidazole (1.5 equiv.) were added. The resulting
mixture was stirred at ambient temperature for about 2 hours, quenched with water and extracted
in dichloromethane. The organic layer was washed with water, brine and dried over anhydrous
sodium sulphate. The solvent was removed and the residue was dissolved in dichloromethane
(5-10 mL) and imidazole (1.5 equiv.) and a compound of Formula RjCHaOH (1.2 equiv.) were
added. The resulting mixture was stirred at an ambient temperature for about 5 hours, quenched
with water and extracted in dichloromethane. The organic layer was washed with water, brine
and dried over anhydrous sodium sulphate. Solvent was removed under pressure and the residue
was purified over silica gel column.
Example 6: Preparation of compound of Formula 14
Compound of Formula 13 (1.0 equiv.) was taken in dry tetrahydrofuran and
tetrabutylammonium Fluoride (1.2 equiv.) was added. After stirring for about 1 hour at an
ambient temperature, solvent was removed under reduced pressure and the residue was extracted
in ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous
sodium sulphate. Solvent was removed and the residue was purified over silica gel column.
Example 7: Preparation of compound of Formula 15
The compound of Formula 15 was prepared using the procedure described for compound
of Formulas.
Example8: Preparation of compound of Formula 17
Compound of Formula 16 (10.0 mmol) was added in portionwise to neat chlorosulfonic
acid (10 mL) at about 0°C. After complete addition resulting mixture was slowly warm to about
50°C for about 12hours. The reaction mixture was poured into ice. Solid was filtered, washed
thoroughly with cold water and dried in vacuum over phosphorus pentachloride to afford
compound of Formula 17.
Example 9: Preparation of compound of Formula 18
Compound of Formula 2 (1.0 equiv.) in pyridine at ambient temperature was added to
compound of Formula 17 (1.0 equiv.). After stirring for about 12 hours the mixture was
evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic
layer was separated, washed with water, dried and evaporated to yield the crude compound of
Formula 18, which was purified over silica gel Chromatography using
methanol/dichloromethane as eluent.
Example 10: Preparation of compound of Formula 19
The compound of Formula 19 was prepared using the procedure described for compound
of Formula 5.
Example 12: Preparation of a compound of Formula 22
To a solution of L-alaninol (1.0 equiv.) in dichloromethane was added di-tert-Butyl
dicarbonate (1.1 equiv.) slowly at about 0-5 °C. The reaction mixture was stirred for about 3
hours at an ambient temperature. The reaction mixture was diluted with dichloromethane and
washed with water, brine, dried over anhydrous sodium sulfate, and evaporated in vacua. The
residue was purified by column chromatography to give the desired product.
Example 13: Preparation of a compound of Formula 23
To a solution of compound of Formula 22 (1.0 equiv.) in ether (20-30 mL) was added
tosyl chloride (1.3 equiv.). The reaction mixture was stirred for about 15 hours and cooled to 0
°C. Potassium hydroxide (about 1.25 equiv., powdered) was added and stirring was continued
for about 15 minutes. Additional 1.25 equiv. of potassium hydroxide was added and again the
reaction mixture was stirred for additional about 15 minutes. The reaction mixture was refluxed
at about 40-50 °C for about 3 hours. The reaction mixture was diluted with water and the
compound was extracted with ethyl acetate. The organic layer was dried and evaporated under
reduced pressure. The product was purified by column chromatography over silica gel to give
the desired compound.
Example 14: Preparation of a compound of Formula 24
In a two-necked round bottom flask Megnesium (50.3 equiv.) was suspended in ether
(100-125 mL), cooled to about 0 °C, added slowly a compound of Formula Cy-Ha (50.3 equiv.),
and diluted with tetrahydrofuran (100-110 mL). A crystal of iodine was added to titrate the
reaction. The reaction mixture was stirred for about 2 hours. The reaction mixture was cooled to
about -40 °C and CuBr-MeaS complex (1.0 equiv.) was added to it. Compound of Formula 23
(10.0 equiv.) dissolved in tetrahydrofuran was added slowly to the reaction mixture. The
reaction mixture was stirred for about 2 hours and quenched by adding saturated ammonium
chloride solution. The reaction mixture was stirred overnight and was extracted with ethyl
acetate. The organic layer was dried and evaporated under reduced pressure. The product was
purified by column chromatography.
Example 15: Preparation of a compound of Formula 25
The deprotection of a compound of Formula 24 to give a compound of Formula 25 was
carried out following the methods well known in the art.
Example 16: Preparation of a compounds of Formulae 35b
The compound of Formula 35a (3.5 equiv.) was dissolved in acetic acid (30-40 mL).
Platinum oxide (1.0 equiv.) was added to it and the suspension was stirred at about 50psi (Hz).
After about 24 hours platinum oxide (2 g) was added and stirred at about 50psi (Hz) pressure.
The reaction mixture was filtered through celite pad. The mother liquor was evaporated to get
the final component (lOgm) as the acetate salt. This was used as such for next step without
further purification. Similarly, the compound of Formula 27 was prepared.
Example 17: Preparation of compound of Formula 29
Potassium carbonate (2.0 equiv.) and benzyl bromide (2.0 equiv.) were added to a
solution of compound of Formula 28 (1.0 equiv.) in dry acetonitrile (5 mL). The resulting
mixture was heated at about 60°C for about 8 hours. The reaction mixture was filtered and
washed with dichloromethane. The filtrate was concentrated and the residue was purified over
silica gel column to afford a compound of Formula 29.
Example 18: Preparation of compound of Formula 30
The compound of Formula 29 (1.0 equiv.) was taken in dry dichloromethane (5 mL) and
cooled to about -20°C. (Diethylamino) sulfur trifluoride (DAST, 1.5 equiv.) was added and the
resulting mixture was slowly warm to about 0°C and stirred for about 2 hours. The reaction
mixture was quenched with saturated aqueous sodium bicarbonate and extracted in
dichloromethane. Organic layer was washed with water, brine and dried over anhydrous sodium
sulphate. The solvent was removed and the residue was purified over silica gel column to afford
a Compound of Formula 30.
Example 19: Preparation of compound of Formula 31
The compound of Formula 30 (1.0 gm, 2.95 mmol) was taken in methanol (15 mL) and
palladium hydroxide (0.2 gm, 20% on carbon) was added. The resulting mixture was stirred
under hydrogen atmosphere for about 12 hours. The reaction mixture was filtered and washed
thoroughly with methanol. The filtrate was concentrated to afford a compound of Formula 31.
Example 20: Preparation of compound of Formula 33
Potassium carbonate (2.0 equiv.) and benzyl bromide (2.0 equiv.) were added to a
solution of compound of Formula 32 (1.0 equiv.) in dry acetonitrile (5 mL). The resulting
mixture was heated at about 60°C for about 8 hours. The reaction mixture was filtered and
washed with dichloromethane. The filtrate was concentrated and the residue was purified over
silica gel column to afford a compound of Formula 33.
Example 21: Preparation of compound of Formula 34
The compound of Formula 33 (1.0 equiv.) was taken in dry dichloromethane (5 mL) and
cooled to about -20°C. (Diethylamino) sulfur trifluoride (DAST, 1.5 equiv.) was added and the
resulting mixture was slowly warm to about 0°C and stirred for about 2 hours. The reaction
mixture was quenched with saturated aqueous sodium bicarbonate and extracted in
dichloromethane. Organic layer was washed with water, brine and dried over anhydrous sodium
sulphate. The solvent was removed and the residue was purified over silica gel column to afford
the compound of Formula 34.
Example 22: Preparation of compound of Formula 35
The compound of Formula 34 (1.0 gm, 2.95 mmol) was taken in methanol (15 mL) and
pallidium hydroxide (0.2 gm, 20% on carbon) was added. The resulting mixture was stirred
under hydrogen atmosphere for about 12 hours. The reaction mixture was filtered and washed
thoroughly with methanol. The filtrate was concentrated to afford a compound of Formula 35.
Example 23: Preparation of a compound of Formula 37
To a solution of compound of Formula 5 (1.0 equiv.) in methanol (20-30 mL) was added
compound of Formula 36 (2.45 equiv.). After stirring for about 1 hour, sodium
cyanoborohydride (2.45 equiv.) was added to the reaction mixture. The reaction mixture was
stirred overnight and then the solvent was evaporated under reduced pressure. The residue was
dissolved in dichloromethane, washed with water, brine and dried over anhydrous sodium
sulfate. The product was purified by column chromatography.
Example 24: Preparation of compound of Formula 38
To a solution of compound of Formula 15 (1.0 equiv.) in methanol (20-30 mL) was
added compound of Formula 25 (2.45 equiv.). After stirring for about 1 hour, sodium
cyanoborohydride (2.45 equiv.) was added to the reaction mixture. The reaction mixture was
stirred overnight and then the solvent was evaporated under reduced pressure. The residue was
dissolved in dichloromethane, washed with water, brine and dried over anhydrous sodium
sulfate. The product was purified by column chromatography.
Example 25: Preparation of a compound of Formula 40
To a solution of compound of Formula 39 (1.0 equiv.) in dichloromethane (75-100 mL)
was added in triethylamine (1.5 equiv.) at an ambient temperature. The reaction mixture was
cooled to about 0°C and di-tert-Butyl dicarbonate (1.2 equiv.) dissolved in 25 mL was added
drop wise and the contents were stirred at an ambient temperature overnight, quenched with
water and extracted in dichloromethane. The solvent was evaporated and the crude product was
purified over silica gel column.
Example 26: Preparation of a compound of Formula 41
The compound of Formula 40 (1.0 equiv.) was taken in methanol (10-15 mL) and cooled
to about 0 °C. To this Raney Nickel (1.0 equiv.) was added, followed by drop wise addition of
hydrazine hydrate (10-15 mL). The reaction mixture was stirred at an ambient temperature for
about 1 hour and filtered through celite pad. Evaporation of filtrate gave the desired compound.
Example 27: Preparation of a compound of Formula 42
The compound of Formula 41(1.0 equiv.) was taken in a round bottom flask and to it
acetonitrile (10ml) was added followed by addition of the compound of Formula 41 a (1.5
equiv.). The reaction mixture was heated at about 70°C for about 10 hours, cooled to room
temperature and water was added. It was then extracted with ethylacetate. Evaporation of
ethylacetate extract followed by column chromatographic purification yielded the desired
product.
Example 28: Preparation of a compound of Formula 42a
The compound of Formula 41 (1.0 equiv.) was dissolved in dichloromethane (10 ml) and
cooled to about 0°C, Hunigs base (diisopropyl ethyl amine) was added to it under argon
atmosphere. The compound of Formula 41b (1.3 equiv.) was added. The reaction mixture was
stirred for about 2 hours from about 0°C to ambient temperature, and washed with water. The
organic phase was dried over anhydrous sodium sulphate and was concentrated in vacua to get
compound of Formula 42a.
Example 29: Preparation of a compound of Formula 43
The compound of Formula 42 (1.54 equiv.) was taken in a round bottomed flask and
cooled to about 0 °C. To this ethanolic hydrochloride (5-10 mL) was added and the reaction
mixture was stirred overnight at an ambient temperature. Evaporation of the solvent gave the salt
of the amine, which was taken in dichloromethane, cooled and basified using triethylamine to
get the free amine. The crude compound of Formula 43 was purified by preparative thin layer
chromatography. Similarly, the compound of Formula 43a was prepared.
Example 30: Preparation of a compound of Formula 46
The compound of Formula 44 (1.0 equiv.) was taken in pyridine (5-10 mL) and cooled to
about 0 °C. To this mixture, thiophene-2-sulphonylchloride (1.2 equiv.) was added in portion
wise and the contents were stirred for about 1 hour at about 0 °C, quenched with water and
extracted in dichloromethane. The organic layer was washed with dilute hydrochloric acid
solution, water and brine and evaporated to get the crude product of Formula 45.
Compound of Formula 45 (1.54 equiv.) was taken in a round bottomed flask and cooled
to about 0 °C. To this ethanolic hydrochloride (5-10 mL) was added and the reaction mixture
was stirred overnight at an ambient temperature. Evaporation of the solvent gave the salt of the
amine, which was taken in dichloromethane, cooled and basified using triethylamine to get the
free amine. The crude product was purified on preparative thin layer chromatography.
Example 31: Preparation of a compound of Formula 47
Cesium carbonate (4.0 equiv.) and thiophenol (3.0 equiv.) were adeed to a solution of
compound of Formula 40 (1.0 equiv.) in acetonitrile (10-20 mL) at an ambient temperature. The
reaction mixture was heated at about 50 C for about 4 hours, cooled to an ambient temperature,
quenched with water and extracted with ethyl acetate. Evaporation of solvent gave the crude
product, which was purified over silica gel column chromatography to form compound of
Formula 47.
Example 32: Preparation of a compound of Formula 49
The amine of Formula 47 (1.0 equiv.) was taken in pyridine (5-10 mL) and cooled to
about 0 °C. To this a compound of Formula 47a (1.2 equiv.) was added in portion wise and the
contents were stirred for about 1 hour at about 0 °C, quenched with water and extracted in
dichloromethane. The organic layer was washed with dilute hydrochloric acid solution, water
and brine and evaporated to get compound of Formula 48.
Compound of Formula 48 (1.0 equiv.) was taken in a round bottom flask and cooled to
about 0 °C. To this mixture, ethanolic hydrochloride (5-10 mL) was added and the reaction
mixture was stirred overnight at ambient temperature. Evaporation of the solvent gave the salt of
the amine, which was taken in dichloromethane, cooled and basified using triethylamine to form
compound of Formula 49, which was purified by preparative thin layer chromatography.
Example 33 : Preparation of a compound of Formula 50
The compound of Formula 47 (1.0 equiv.) was taken in a round bottom flask and to it
acetonitrile (10 mL) was added followed by addition of the compound of Formula 41 a (1.5
equiv.). The reaction mixture was heated at about 70°C for about 10 hours, cooled to ambient
temperature and water was added to it and extracted with ethylacetate. The solvent was
evaporated and the product thus formed was purified by column chromatography.
Example 34: Preparation of a compound of Formula 51
The compound of formula 50 (3.0 mmol, 0.8 g) was taken in a round bottom flask and
cooled to about 0°C. To this ethanolic hydrochloric acid (40 mL) was added and the reaction
mixture was allowed to stir at ambient temperature for about 5 hours, the solvent was evaporated
and the residue was taken in dichloromethane, cooled to about 0°C and neutralized with
triethylamine. It was then stirred at ambient temperature for about 1 hour, quenched with water
and extracted with dichloromethane. The solvent was evaporated and the product thus formed
was purified by preparative thinlayer chromatography.
Example 35: Preparation of a compound of Formula 53
Triethylamine (1.5 equiv.) and phenylchloroformate (1.2 equiv.) were added to a solution
of compound of formula 52 (1.0 equiv.) in dichloromethane (30 mL) dropwise, cooled to about
0°C and stirred for about 2 hours. The reaction mixture was diluted with dichloromethane,
washed with water, dried over anhydrous sodium sulphate and evaporated in vacua to form the
compound of formula 53.
Example 36: Preparation of a compound of Formula 54
A mixture of compound of formula 53 (1.0 equiv.), hydrazine hydrate (2.5 equiv.) and
1,4-dioxane were stirred at about 80°C for about 2 hours. The reaction mixture was evaporated
in vacuo. The residue was diluted with dichloromethane, washed with water, dried over
anhydrous sodium sulphate and evaporated in vacuo to form the compound of formula 54.
Example 37: Preparation of a compound of Formula 55
A mixture of compound of formula 54 (1.0 equiv.), formamidine acetate (3 equiv.),
acetic acid (3 equiv.) and dimethylformamide (20 mL) were stirred at about 80°C for about 3
hours. The reaction mixture was diluted with ethylacetate, washed with water dried over
anhydrous sodium sulphate and evaporated in vacuo. The product was purified by column
chromatography in ethyl acetate and hexane to form the compound of formula 55.
Example 38: Preparation of a compound of Formula 56
35
Compound of Formula 55 (1.0 equiv.) was taken in a round bottom flask and cooled to
about 0°C. To this mixture, ethanolic hydrochloride (5-10 mL) was added and the reaction
mixture was stirred overnight at ambient temperature. Evaporation of the solvent gave the salt of
the amine, which was taken in dichloromethane, cooled and basified using triethylamine to form
compound of Formula 56, which was purified by preparative thin layer chromatography.
The following compounds were prepared analogously, following the above general
procedures:
Compound No.l: AA-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-benzofuran-2-
sulfonamide, Mass (m/z): 427.5; m.pt: Gummy;
Compound No. 2: N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1 -
benzofuran-2-sulfonamide, Mass (m/z): 413.00; m.pt: 58-61°C;
Compound No. 3: N- [3 -({[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-4-yl]thiophene-2-
sulfonamide, Mass (m/z): 394.5; m.pt: Gummy;
Compound No.4: 2-amino-N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1Hbenzimidazole-
5-sulfonamide, Mass (m/z): 442.04; m.pt: 83-85°C;
Compound No.5: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]guanidine,
Mass (m/z): 290.40; m.pt: Gummy;
Compound No.6: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(5-oxo-l,5-
dihydro-4H-l,2,4-triazol-4-yl)benzenesulfonamide, Mass (m/z): 470.4; m.pt: Gummy;
Compound No.7: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(5-methyll,
3,4-oxadiazol-2-yl)benzenesulfonamide, Mass (m/z): 469.04; m.pt: 62-64 C;
Compound No. 8: N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -4-( 1 -
methyl-lH-pyrazol-4-yl)benzenesulfonamide, Mass (m/z): 453.2; m.pt: 65-67°C;
Compound No.9: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(3,5-
dimethylisoxazol-4-yl)benzenesulfonamide, Mass (m/z): 482.1; m.pt: Gummy;
Compound No. 10: N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -5-(3,5
dimethylisoxazol-4-yl)thiophene-2-sulfonamide, Mass (m/z): 488.0; m.pt: Gummy;
Compound No.l 1: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-
dimethylisoxazol-4-yl)thiophene-2-sulfonamide, Mass (m/z): 473.9; m.pt: 61-62 C;
Compound No. 12: N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-3-
[(methylsulfonyl)amino]benzenesulfonamide, Mass (m/z): 480.3; m.pt: 55-57°C;
Compound No. 13: N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-
{[(dimethylamino)sulfonyl]amino}benzenesulfonamide, Mass (m/z): 509.20; m.pt: 53-56°C;
Compound No. 14: N-[3-({[2-cyclohexyl-1 -methylethyl]amino}methyl)pyridin-4-yl]-1 -
benzothiophene-2-sulfonamide, Mass (m/z): 444.6; m.pt: 89.9-94.3°C;
Compound No. 15: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-5- {[(1 -methyl -
lH-imidazol-4-yl)sulfonyl]amino}pyridine-2-sulfonamide, Mass (m/z): 546.97; m.pt: Gummy;
Compound No. 16: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl] -5 -
[(methylsulfonyl)amino]pyridine-2-sulfonamide, Mass (m/z): 546.97; m.pt: Gummy;
Compound No. 17: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-[(2-
thienylsulfonyl)amino]pyridine-2-sulfonamide, Mass (m/z): 548.93; m.pt: 123-126°C;
Compound No. 18: 5-bromo-N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-1,3-
thiazole-2-sulfonamide, Mass (m/z): 472.1; m.pt: 74-75°C;
Compound No.19: [5-(2-thienyl)isoxazol-3-yl]methyl [2-({[(lS)-2-cyclopentyl-lmethylethyl]
amino}methyl)phenyl]carbamate, Mass (m/z): 440.2; m.pt: Gummy;
Compound No.20: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-2-fluoro-5-(1Hpyrrol-
l-yl)benzenesulfonamide, Mass (m/z): 470.3; m.pt: 65-66°C;
Compound No.21: 2-amino-N-[2-({ [2-cyclohexyl-1-methyl ethyl] amino }methyl)phenyl]-1,3-
benzothiazole-4-sulfonamide, Mass (m/z): 459.30; m.pt: 58-60°C;
Compound No.22: N-[2-({[2-({[2-cyclohexyl-lmethylethyl]
amino}methyl)phenyl]amino}sulfonyl)phenyl]thiophene-3-sulfonamide, Mass
(m/z): 548.30; m.pt: 85-87°C;
Compound No.23: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-
(IH-tetrazol-l-yl)benzenesulfonamide, Mass (m/z): 394.2; m.pt: 146-148°C;
Compound No.24: N-[2-({[(2S)-2-cyclohexyl-2-hydroxy-l-methylethyl]amino}methyl)phenyl]-
4-(lH-pyrrol-l-yl)benzenesulfonamide, Mass (m/z): 468.3; m.pt: 106-108°C;
Compound No.25: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(l,3-
oxazol-5-yl)benzenesulfonamide, Mass (m/z): 440.4; m.pt: 58-60°C;
Compound No.26: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-6-( 1Hl,
2,4-triazol-l-yl)pyridine-3-sulfonamide, Mass (m/z): 441.2; m.pt: 153-155°C;
Compound No.27: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)pyridin-3-yl]thiophene-
2-sulfonamide, Mass (m/z): 394.2; m.pt: 56-58°C;
Compound No.28: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-
(lH-l,2,4-triazol-l-yl)benzenesulfonamide, Mass (m/z): 458.4; m.pt: 122-124°C;
Compound No.29: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-( 1H-1,2,4-
triazol-l-yl)pyridine-3-sulfonamide, Mass (m/z): 455.3; m.pPt: 108-109°C;
Compound No.30: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lHtetrazol-
l-yl)benzenesulfonamide, Mass (m/z): 445.3; m.pt: 175-176 C;
Compound No.31: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-( 1 H-pyrrol-1 -
yl)pyridine-3-sulfonamide, Mass (m/z): 453.3; m.pt: 98-100°C;
Compound No.32: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)pyridin-3-yl]-3-fluoro-4-
(lH-l,2,4-triazol-l-yl)benzenesulfonamide, Mass (m/z): 473.6; m.pt: 62-64°C;
Compound No.33: N-[2-({[2-cyclohexyl-2-fluoro-lmethylethyl]
amino}methyl)phenyl]thiophene-2-sulfonamide, Mass (m/z): 411.0; m.pt: Gummy;
Compound No.34: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lHpyrrol-
l-yl)pyridine-3-sulfonamide, Mass (m/z): 439.0; m.pt: 149-151°C;
Compound No.35: N-[3-({[2-cyclohexyl-1 -methylethyl]amino}methyl)pyridin-4-yl] -5 -isoxazol-
5-ylthiophene-2-sulfonamide hydrochloride, Mass (m/z): 497.62; m.pt: 146-150°C;
Compound No.36: 2-amino-N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl] amino }methyl)phenyl]-
l,3-benzothiazole-6-sulfonamide, Mass (m/z): 444.94; m.pt: 61-63°C;
Compound No.37: 2-amino-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-
lH-benzimidazole-6-sulfonamide, Mass (m/z): 427.96; m.pt: 109-110°C;
Compound No.38: 5-{[amino(imino)methyl]amino}-N-[2-({[2-cyclohexyl-lmethylethyl]
amino}methyl)phenyl]pyridine-2-sulfonamide, Mass (m/z): 446.00; m.pt: Gummy;
Compound No.39: N-[4-({[2-({ [2-cyclohexyl-1-
methylethyl]amino} methyl )phenyl] amino} sulfonyl)-3 -methoxyphenyl] -1 -methyl-1 H-imidazole-
4-sulfonamide, Mass (m/z): 576.5; m.pt: Gummy;
Compound No.40: N-[6-({[2-({[2-cyclohexyl-1 -methylethyljamino}methyl)
phenyl]amino}sulfonyl)-l,3-benzothiazol-2-yl]acetamide, Mass (m/z): 501.2; m.pt: 78-80°C;
Compound No.41: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-methyl-lHbenzimidazole-
2-sulfonamide, Mass (m/z): 441.03; m.pt: 129-131°C;
Compound No.42: 4-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-
fluorobenzenesulfonamide, Mass (m/z): 420; m.pt: 58.4-60.2°C;
Compound No.43: 4-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-
methoxybenzenesulfonamide, Mass (m/z): 432.5; m.pt: Gummy;
Compound No.44: N-[4-({[2-({[2-cyclohexyl-lmethylethyl]
amino} methyl)phenyl] amino} sulfonyl)-3 -methoxyphenyl] acetamide, Mass (m/z):
474.02; m.pt: 82-85°C;
Compound No.45: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-2-methoxy-4-
[(methylsulfonyl)amino]benzenesulfonamide, Mass (m/z): 510; m.pt: Gummy;
Compound No.46: Methyl [4-({[2-({[2-cyclohexyl-1-methylethyl]amino}methyl)
phenyl]amino}sulfonyl)phenyl]carbamate, Mass (m/z): 460.00; m.pt: 44-46°C;
Compound No.47: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-( 1,2,3-
thiadiazol-4-yl)benzenesulfonamide, Mass (m/z): 456.90; m.pt: 142-144°C;
Compound No.48: N-[2-({ [2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(2-methyl-2Htetrazol-
5-yl)benzenesulfonamide, Mass (m/z): 468.99; m.pt: 58-60°C;
Compound No .49: N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -4-(2-
methyl-2H-tetrazol-5-yl)benzenesulfonamide, Mass (m/z): 454.94; m.pt: 55-57°C;
Compound No.50: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-4-(5-
methyl-l,3,4-oxadiazol-2-yl)benzenesulfonamide, Mass (m/z): 455.01; m.pt: 83-85°C;
Compound No.51: N-[2-( {[2-cyclohexyl-1-methylethyl] amino }methyl)pheny l]-6-(2-
furyl)pyridine-3-sulfonamide, Mass (m/z): 453.9; m.pt: 94-95°C;
Compound No.52: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-6-(2-
furyl)pyridine-3-sulfonamide, Mass (m/z): 439.9; m.pt: 64-65°C;
Compound No.53: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-(3-
furyl)pyridine-3-sulfonamide, Mass (m/z): 454.0; m.pt: 70-72°C;
Compound No.54: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(3-
furyl)pyridine-3-sulfonamide, Mass (m/z): 439.9; m.pt: 68-70°C;
Compound No.55: N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-1 -methyl-2-oxol,
2-dihydroquinoline-6-sulfonamide, Mass (m/z): 468.0; m.pt: 55-57°C;
Compound No.56: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l-methyl-
2-oxo-l,2-dihydroquinoline-6-sulfonamide, Mass (m/z): 454.0; m.pt: 68-69°C;
Compound No.57: N-[2-({ [2-cyclohexyl-l-methylethyl]amino}memyl)phenyl]-6-(lH-tetrazoll-
yl)pyridine-3-sulfonamide, Mass (m/z): 455.9; m.pt: 119-121°C;
Compound No.58: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-6-( 1Htetrazol-
l-yl)pyridine-3-sulfonamide, Mass (m/z): 442.0; m.pt: 142-144°C;
Compound No.59: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-
thienyl)pyridine-3-sulfonamide, Mass (m/z): 469.9; m.pt: 91-92°C;
Compound No.60: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]aniino}methyl)phenyl]-6-(2-
thienyl)pyridine-3-sulfonamide, Mass (m/z): 455.9; m.pt: 62-64°C;
Compound No.61: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-imidazoll-
yl)pyridine-3-sulfonamide, Mass (m/z): 454.0; m.pt: 119-120°C;
Compound No.62: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lHimidazol-
l-yl)pyridine-3-sulfonamide, Mass (m/z): 440.0; m.pt: 68-69°C;
Compound No.63: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-methyl-l,3-
thiazol-4-yl)benzenesulfonamide, Mass (m/z): 484.0; m.pt: 88-89°C;
Compound No.64: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-(2-
methyl-l,3-thiazol-4-yl)benzenesulfonamide, Mass (m/z): 470.0; m.pt: Gummy;
Compound No.65: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-fluoro-3-
methyl-l-benzothiophene-2-sulfonamide, Mass (m/z): 474.9; m.pt: 131-132°C;
Compound No.66: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-5-fluoro-3-
methyl-l-benzothiophene-2-sulfonamide, Mass (m/z): 461.0; m.pt: 64-65°C;
Compound No.67: N-[2-({[2-cyclohexyl-2-fluoro-1 -methylethyl]amino}methyl)phenyl]-2-
(trifluoroacetyl)-l,2,3»4-tetrahydroisoquinoline-7-sulfonamide, Mass (m/z): 556.0; m.pt:
Gummy;
Compound No.68: N-[4-({[2-({[2-cyclohexyl-2-fluoro-1 -methylethyl]amino} methyl)
phenyl]amino}sulfonyl)phenyl]thiophene-2-sulfonamide, Mass (m/z): 565.9; m.pt: 85-86°C;
Compound No.69: N-[2-({[2-cyclohexyl-2-fluoro-1 -methylethyl]amino}methyl)phenyl]-4-( 1Hpyrrol-
l-yl)benzenesulfonamide, Mass (m/z): 470.1; m.pt: 80-81°C;
Compound No.70:N-(2-{ [(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)-2-
(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide, Mass (m/z): 556.0; m.pt: 65-
66°C;
Compound No.71: N-(4-{[(2-{[(3-cyclohexyl-2-fluoropropyl)amino]methyl}
phenyl)amino]sulfonyl}phenyl)thiophene-2-sulfonamide, Mass (m/z): 565.9; m.pt: 69-70°C;
Compound No.72: 5-amino-N-[2-({[2-cyclohexyl-lmethylethyl]
amino}methyl)phenyl]pyridine-2-sulfonamide, Mass (m/z): 403.01; m.pt: Gummy;
Compound No.73: 5-chloro-N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-
2,l,3-benzoxadiazole-4-sulfonamide, Mass (m/z): 462.89; m.pt: Gummy;
Compound No.74: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-1 -
benzothiophene-2-carboxamide, Mass (m/z): 407.08; m.pt: Gummy;
Compound No.75: N-(2- {[(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)thiophene-2-
sulfonamide, Mass (m/z): 435.1; m.pt: Gummy;
Compound No.76: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-2,l,3-
benzothiadiazole-5-sulfonamide, Mass (m/z): 430.95; m.pt: Gummy;
Compound No.77: N-[4-({[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl] amino}
sulfonyl)-3-methoxyphenyl]thiophene-2-sulfonamide, Mass (m/z): 577.93; m.pt: 101-103°C;
Compound No.78: N-[4-({[2-({[2-cyclohexyl-lmethylethyl]
amino}methyl)phenyllamino}sulfonyl)-3-hydroxyphenyl]thiophene-2-sulfonamide,
Mass (m/z): 563.94; m.pt: 147-150°C;
Compound No.79: N-[4-({[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]amino}
sulfonyl)-3-hydroxyphenyl]acetamide, Mass (m/z): 459.97; m.pt: 118-120°C;
Compound No. 80: N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-(2-
oxo-l,3-oxazolidin-3-yl)benzenesulfonamide, Mass (m/z): 489.98; m.pt: 141-142°C;
Compound No.81: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-
(2-oxo-l,3-oxazolidin-3-yl)benzenesulfonamide, Mass (m/z): 475.94; m.pt: 130-131 C;
Compound No. 82: N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1Hl,
2,3-triazol-l-yl)benzenesulfonamide, Mass (m/z): 471.99; m.pt: 124-125°C;
Compound No.83: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino} methyl)phenyl] -3-fluoro-4-
(lH-l,2,3-triazol-l-yl)benzenesulfonamide, Mass (m/z): 457.96; m.pt: 110-111°C;
Compound No.84: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-1 -
(trifluoroacetyl)indoline-5-sulfonamide, Mass (m/z): 524.6; m.pt: 94.2-103°C;
Compound No.85: N-[2-( {[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl] indoline-5-
sulfonamide, Mass (m/z): 428.2; m.pt: 92.8-94.56C;
Compound No.86: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(l,2,4-
oxadiazol-3-yl)benzenesulfonamide, Mass (m/z): 455.01; m.pt: 52-54°C;
Compound No.87: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-4-( 1,2,4-
oxadiazol-3-yl)benzenesulfonamide, Mass (m/z): 441.02; m.pt: 128-130°C;
Compound No.88: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl] -3,4-
difluorobenzenesulfonamide, Mass (m/z): 409.01; m.pt: 78-80°C;
Compound No.89: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)pyridin-3-yl]-4-(5-
methyl-l,3,4-oxadiazol-2-yl)benzenesulfonamide, Mass (m/z): 470.03; m.pt: 64-66 C;
Compound No.90:N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(lHl,
2,3-triazol-l-yl)benzenesulfonamide, Mass (m/z): 440.04; m.pt: 149-1506C;
Compound No.91: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lHpyrazol-
l-yl)benzenesulfonamide, Mass (m/z): 471.01; m.pt: 62-63°C;
Compound No.92: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-
(IH-pyrazol-l-yl)benzenesulfonamide, Mass (m/z): 456.97; m.pt: 123-124T;
Compound No.93: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-pyrrolidin-1 -
ylpyridine-3-sulfonamide, Mass (m/z): 457.1; m.pt: 110-111°C;
Compound No.94: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-6-
pyrrolidin-l-ylpyridine-3-sulfonamide, Mass (m/z): 443.0; m.pt: 104-106°C;
Compound No.95: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl] -6-morpholin-4-
ylpyridine-3-sulfonamide, Mass (m/z): 473.0; m.pt: Gummy;
Compound No.96: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-6-
morpholin-4-ylpyridine-3-sulfonamide, Mass (m/z): 459.0; m.pt: Gummy;
Compound No.97: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-1 -ethyl-2-oxol,
2-dihydroquinoline-6-sulfonamide, Mass (m/z): 482.0; m.pt: 81-82°C;
Compound No.98: N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l-ethyl-2-
oxo-l,2-dihydroquinoline-6-sulfonamide, Mass (m/z): 468.0; m.pt: 70-71°C;
Compound No.99: N-[2-({[(1 S)-2-cyclopentyl-1 -methylethyl]amino}methyl)phenyl]-2-oxo-1,2-
dihydroquinoline-6-sulfonamide, Mass (m/z): 440.0; m.pt: 83-84°C;
Compound No. 100: 6-bromo-AL[2-({ [2-cyclohexyl-1 -methylethyllamino}methyl)
phenyl]pyridine-3-sulfonamide, Mass (m/z): 465.9; m.pt: 120-121 C;
Compound No. 101: 2-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)
phenyl]pyrimidine-5-sulfonamide, Mass (m/z): 404.00; m.pt: 142-144°C;
Compound No.102: 6-amino-N-[2-({ [2-cyclohexyl-1-
methylethyl]amino}methyl)phenyl]pyridine-3-sulfonamide, Mass (m/z): 403.00; m.pt: 54-56°C;
Compound No. 103: N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-2,3-
dihydro-l,3-benzoxazole-6-sulfonamide, Mass (m/z): 443.9; m.pt: 167-169°C;
Compound No. 104: 5-chloro-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l,3-
benzothiazole-2-sulfonamide, Mass (m/z): 477.83; m.pt: 79-82°C;
CompoundNo.105: 5 -chloro-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]
amino}methyl)phenyl]-l,3-benzothiazole-2-sulfonamide, Mass (m/z): 463.82; m.pt: 69-72°C;
Compound No. 106: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-2-
(dimethylamino)-l,3-benzothiazole-6-sulfonamide, Mass (m/z): 486.88; m.pt: Gummy;
Compound No. 107: N-[6-({ [2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)
phenyl] amino} sulfonyl)-1,3 -benzothiazol-2-yl] -L-alaninamide,
Mass (m/z): 456.00; m.pt: 93-95°C;
Compound No. 108: N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-oxo-3,4-
dihydroquinazoline-2-sulfonamide, Mass (m/z): 529.93; m.pt: Gummy;
Compound No. 109: N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methy l)phenyl] -2-
(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide, Mass (m/z): 537.9; m.pt: 55-
56°C;
Compound No.l 10: N-[2-({[2-cyclohexyl-1-methylethyl]amino}methyl)phenyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide, Mass (m/z): 441.9; m.pt: 116-117 C;
Compound No.l 11: N-[2-({[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-2-oxo-1,2-
dihydroquinoline-6-sulfbnamide, Mass (m/z): 454.0; m.pt: 107-108°C;
Compound No.l 12: N-[2-({[2-cyclohexyl-1-methylethyl]amino}methyl)phenyl]-3-fluoro-4-
(IH-imidazol-l-yl)benzenesulfonamide, Mass (m/z): 471.06; m.pt: 70-72°C.
Compound No.l 13: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-fluoro-
3-methyl-l-benzothiophene-2-sulfonamide, Mass (m/z): 475.0; m.pt: 81-82°C;
Compound No.l 14: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-methyl-
2-oxo-l,2-dihydroquinoline-6-sulfonamide, Mass (m/z): 467.9; m.pt: 84-86°C;
Compound No.l 15: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-ethyl-2-
oxo-l,2-dihydroquinoline-6-sulfonamide, Mass (m/z): 481.9; m.pt: 87-88°C;
Compound No.l 16: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-
thienyl)pyridine-3-sulfonamide, Mass (m/z): 469.8; m.pt: 85-87°C;
Compound No.l 17: N-[2-({[(lS)-2-cyclohexyl-l-methylethyllamino}methyl)phenyl]-6-(2-
furyl)pyridine-3-sulfonamide, Mass (m/z): 453.9; m.pt: 66-67 C;
Compound No.l 18: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(lHtetrazol-
l-yl)pyridine-3-sulfonamide, Mass (m/z): 455.8; m.pt: 158-159°C;
Compound No.l 19: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-
pyrrolidin-l-ylpyridine-3-sulfonamide, Mass (m/z): 456.9; m.pt: 108-109°C;
Compound No. 120: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-
methyl-l,3-thiazol-4-yl)benzenesulfonamide, Mass (m/z): 483.9; m.pt: Gummy;
Compound No.121: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-
dimethylisoxazol-4-yl)thiophene-2-sulfonamide, Mass (m/z): 487.8; m.pt: 84-86°C;
Compound No. 122: N-[2-({[(1 S)-2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-4-(5 -
methyl-l,3,4-oxadiazol-2-yl)benzenesulfonamide, Mass (m/z): 468.89; m.pt: 94-96°C;
Compound No. 123: N-[2-({[(1 S)-2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-4-( 1,2,4-
oxadiazol-3-yl)benzenesulfonamide, Mass (m/z): 454.93; m.pt: 106-108°C;
Compound No. 124: N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-
4-(lH-pyrazol-l-yl)benzenesulfonamide, Mass (m/z): 470.91; m.pt: 60-62°C.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention.
Microbiological activity
Microbroth minimum inhibitory concentration (MIC) was performed using NCCLS
method in Cation adjusted Mueller Hinton broth for facultative cultures (S.aureus,
Enterococcus) and Cation adjusted Mueller Hinton broth +2.5% lysed horse blood for
S.pneumoniae. MIC against H.influenzae strains was performed by NCCLS broth dilution
method using HTM broth. Overnight grown cultures were adjusted to 0.5 Mcfarland using
normal saline and diluted 100 times. 1 mg/ml concentration of stock solution of drug in
DMSO/distilled water/solvent given in NCCLS manual were prepared. NCCLS double dilutions
were done to get the required concentration range of the drugs in the 96 well microtiter plates
using the respective media. 100 ul of culture broth was added in wells already containing 100 ul
of broth containing antibiotic to get approximately 3-7x10^ CFU/ml. The plates were incubated
at 37°C for about 18-24 hours. The concentration of drug at which there was complete
disappearance of growth was considered as MIC.
Compounds of this invention have shown good activity againsts microbial strains. Some
of the compounds described herein have shown very good activity against microbial strains, for
example, Streptococcus pneumoniae, Haemophilius influenzae, Streptococcus pyogenes or
Staphylococcus aureus.

WE CLAIM:
1. A compound having the structure of Formula I,
(Figure Removed)
Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Cy is cyclohexyl or cyclopentyl;
X is -CH2CH(CH3)-, -CH(F)CH(CH3)-, -CH(OH)CH(CH3)- or -CH2CH(F)CH2-;
Y is NH;
Z is -CH2-;
Xi and X2 are independently CH or N;
R is NHC(NH)NH2, NHCOOCH2R! or NHSO2R2;
RI can be 5-(2-thienyl)isoxazolyl;
R2 can be aryl, heteroaryl or heterocyclyl.
2. A compound, which is:
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1 -benzofuran-2-
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l -methylethyl] amino }methyl)phenyl]-1-benzofuran-2-
sulfonamide,
N-[3-({[2-cyclohexyl-l-methylethyl]amino}methyl)pyridin-4-yl]thiophene-2-
sulfonamide,
2-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-lH-benzimidazole-
5-sulfonamide,
N- [2 -({[2-cyc lohexyl-1 -methylethyl] amino} methyl)phenyl] guanidine,
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-4-(5-oxo-1,5-dihydro-4Hl,
2,4-triazol-4-yl)benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-(5 -methyl-1,3,4-
oxadiazol-2-yl)benzenesulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -4-( 1 -methyl-1Hpyrazol-
4-yl)benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-(3,5-dimethylisoxazol-
yl)benzenesulfonamide,
45
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-dimethylisoxazol-4-
yl)thiophene-2-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-
dimethylisoxazol-4-yl)thiophene-2-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -3 -
[(methylsulfonyl)amino]benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-
{[(dimethylamino)sulfonyl]amino}benzenesulfonamide,
N-[3-({[2-cyclohexyl-l-methylethyl]amino}methyl)pyridin-4-yl]-l-benzothiophene-2-
sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -5- {[(1 -methyl-1 H-imidazol-
4-yl)sulfonyl] amino }pyridine-2-sulfonamide,
N-[2-({ [2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-
[(methylsulfonyl)amino]pyridine-2-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-[(2-
thienylsulfonyl)amino]pyridine-2-sulfonamide,
5 -bromo-N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,3-thiazole-2-
sulfonamide,
[5-(2-thienyl)isoxazol-3-yl]methyl [2-({[(lS)-2-cyclopentyl-lmethylethyl]
amino}methyl)phenyl]carbamate,
N-[2-( {[2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-2-fluoro-5-(l H-pyrrol-1 -
yl)benzenesulfonamide,
2-amino-N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,3 -benzothiazole-
4-sulfonamide,
N-[2-({[2-({ [2-cyclohexyl-1-
methylethyl] amino} methyl)phenyl] amino} sulfonyl)phenyl] thiophene-3 -sulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1Htetrazol-
1 -yl)benzenesulfonamide,
N- [2-( {[(2 S)-2-cyclohexyl-2-hydroxy-1 -methylethyl] amino} methyl)phenyl] -4-( 1Hpyrrol-
1 -yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(l,3-oxazol-5-
yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-l,2,4-triazol-lyl)
pyridine-3-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )pyridin-3 -yl] thiophene-2-
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-l,2,4-
triazol-1 -yl)benzenesulfonamide,
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-(l H-1,2,4-triazol-1 -
yl)pyridine-3-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-tetrazol-lyl)
benzenesulfonamide,
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-6-( 1 H-pyrrol-1 -yl)pyridine-
3-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-3 -yl] -3-fluoro-4-( 1 H-1,2,4-
triazol- 1 -yl)benzenesulfonamide,
N-[2-({[2-cyclohexyl-2-fluoro-l-methylethyl]amino}methyl)phenyl]thiophene-2-
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-pyrrol-lyl)
pyridine-3-sulfonamide,
N-[3-({[2-cyclohexyl-l-methylethyl]amino}methyl)pyridin-4-yl]-5-isoxazol-5-
ylthiophene-2-sulfonamide hydrochloride,
2-amino-N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1,3-
benzothiazole-6-sulfonamide,
2-amino-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-lHbenzimidazole-
6-sulfonamide,
5- {[amino(imino)methyl]amino} -N-[2-( {[2-cyclohexyl-1 -
methylethyl] amino }methyl)phenyl]pyridine-2-sulfonamide,
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
methoxyphenyl] -1 -methyl-1 H-imidazole-4-sulfonamide,
N-[6-( {[2-( {[2-cyclohexyl-1 -methylethyl]amino} methyl)phenyl] amino} sulfonyl)-1,3-
benzothiazol-2-yl]acetamide,
N-[2-({ [2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-methyl-lHbenzimidazole-
2-sulfonamide,
4-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-
fluorobenzenesulfonamide,
4-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-
methoxybenzenesulfonamide,
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
methoxyphenyl] acetamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-methoxy-4-
[(methylsulfonyl)amino]benzenesulfonamide,
Methyl [4-({[2-({[2-cyclohexyl-1 -
methylethyl] amino} methyl)pheny 1] amino} sulfonyl)phenyl] carbamate,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(l,2,3-thiadiazol-4-
yl)benzenesulfonamide,
N-[2-({ [2-cyclohexyl-1 -methylethyl]amino}methyl)phenyl]-4-(2-methyl-2H-tetrazol-5-
yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(2-methyl-2Htetrazol-
5-yl)benzenesulfonamide,
N-[2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -4-(5 -methyl-1,3,4-
oxadiazol-2-yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-furyl)pyridine-3-
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(2-furyl)pyridine-3-
sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -6-(3-furyl)pyridine-3-
sulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -6-(3 -furyl)pyridine-3-
sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -1 -methyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -1 -methyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -6-( 1 H-tetrazol-1 -
yl)pyridine-3-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl] amino }methyl)phenyl]-6-(l H-tetrazol-1-
yl)pyridine-3-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-thienyl)pyridine-3-
sulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -6-(2 -thienyl)pyridine-
3-sulfonamide,
N- [2-( { [2-cyclohexyl- 1 -methylethyl] amino } methyl )phenyl] -6-( 1 H-imidazol- 1 -
yl)pyridine-3-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-(lH-imidazol-lyl)
pyridine-3-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-methyl-l,3-thiazol-4-
yl)benzenesulfonamide,
N-[2-( { [( 1 S)-2-cyclopentyl- 1 -methylethyl] amino } methyl)phenyl] -3 -(2 -methyl- 1,3-
thiazol-4-yl)benzenesulfonamide,
N-[2-( { [2-cyclohexyl- 1 -methylethyl] amino } methyl)phenyl] -5 -fluoro-3 -methyl- 1 -
benzothiophene-2-sulfonamide,
N- [2-( { [( 1 S)-2-cyclopentyl- 1 -methylethyl] amino } methyl)phenyl] -5 -fluoro-3 -methyl- 1 -
benzothiophene-2-sulfonamide,
N- [2-( { [2-cyclohexyl-2-fluoro- 1 -methylethyl] amino } methyl)phenyl] -2-(trifluoroacetyl)-
l,2,3,4-tetrahydroisoquinoline-7-sulfonamide,
-({ [2-cyclohexyl-2-fluoro- 1 -
methylethyl]amino}methyl)phenyl]amino}sulfonyl)phenyl]thiophene-2-sulfonamide,
N- [2-( { [2-cyclohexyl-2-fluoro- 1 -methylethyl] amino } methyl)phenyl] -4-( 1 H-pyrrol- 1 -
yl)benzenesulfonamide,
N-(2-{[(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)-2-(trifluoroacetyl)-l, 2,3,4-
tetrahydroisoquinoline-7-sulfonamide,
N-(4- { [(2- { [(3-cyclohexyl-2-
fluoropropyl)amino]methyl}phenyl)amino]sulfonyl}phenyl)thiophene-2-sulfonamide,
5-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-2-
sulfonamide,
5 -chloro-N- [2-( { [( 1 S)-2-cyclopentyl- 1 -methylethyl] amino } methyl)phenyl] -2,1,3-
benzoxadiazole-4-sulfonamide,
N- [2-( { [( 1 S)-2-cyclopentyl- 1 -methylethyl] amino } methyl)phenyl] - 1 -benzothiophene-2-
carboxamide,
N-(2-{[(3-cyclohexyl-2-fluoropropyl)amino]methyl}phenyl)thiophene-2-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-2,l,3-
benzothiadiazole-5-sulfonamide,
N- [4-( { [2-( { [2-cyclohexyl- 1 -methylethyl] amino } methyl)phenyl] amino } sulfonyl)-3 -
methoxyphenyl]thiophene-2-sulfonamide,
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3-
hydroxyphenyl]thiophene-2-sulfonamide,
N- [4-( {[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] amino} sulfonyl)-3 -
hydroxyphenyl] acetamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-(2-oxo-1,3-
oxazolidin-3-yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(2-oxo-l,3-
oxazolidin-3-yl)benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -3 -fluoro-4-( 1H-1,2,3 -
triazol-1 -yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-l,2,3-
triazol-l-yl)benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1 -(trifluoroacetyl)indoline-
5-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]indoline-5-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(l,2,4-oxadiazol-3-
yl)benzenesulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl] amino} methyl)phenyl] -4-( 1,2,4-oxadiazol-3-
yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-3,4-
difluorobenzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)pyridin-3 -yl] -4-(5 -methyl-1,3,4-
oxadiazol-2-yl)benzenesulfonamide (compound No.89),
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-4-(lH-l,2,3-triazol-lyl)
benzenesulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-fluoro-4-(lH-pyrazol-lyl)
benzenesulfonamide,
N- [2-( {[(1 S)-2-cyclopentyl-1 -methylethyl]amino} methyl)phenyl] -3 -fluoro-4-( 1Hpyrazol-
1 -yl)benzenesulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-pyrrolidin-1 -ylpyridine-3 -
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-pyrrolidin-lylpyridine-
3-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-morpholin-4-ylpyridine-3-
sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-6-morpholin-4-
ylpyridine-3-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl )phenyl] -1 -ethyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l-ethyl-2-oxo-l,2-
dihydroquinoline-6.-sulfonamide,
N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-l,2-
dihydroquinoline-6-sulfonamide,
6-bromo-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-3-
sulfonamide,
2-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyrimidine-5-
sulfonamide,
6-amino-N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]pyridine-3-
sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-2,3-dihydro-l,3-
benzoxazole-6-sulfonamide,
5 -chloro-N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,3 -benzothiazole-
2-sulfonamide,
5-chloro-N-[2-({[(lS)-2-cyclopentyl-l-methylethyl]amino}methyl)phenyl]-l,3-
benzothiazole-2-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -2-(dimethylamino)-1,3-
benzothiazole-6-sulfonamide,
N-[6-({[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]amino}sulfonyl)-l,3-
benzothiazol-2-yl]-L-alaninamide,
N-[2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-oxo-3,4-
dihydroquinazoline-2-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -2-(trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide,
N-[2-({[2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-2-oxo-l,2-dihydroquinoline-
6-sulfonamide,
N- [2-( {[2-cyclohexyl-1 -methylethyl]amino} methyl)phenyl] -3 -fluoro-4-( 1 H-imidazol-1 -
yl)benzenesulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -5 -fluoro-3 -methyl-1 -
benzothiophene-2-sulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-l-methyl-2-oxo-l,2-
dihydroquinoline-6-sulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -1 -ethyl-2-oxo-1,2-
dihydroquinoline-6-sulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-6-(2-thienyl)pyridine-
3-sulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -6-(2 -furyl)pyridine-3 -
sulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl]amino} methyl)phenyl] -6-( 1 H-tetrazol-1 -
yl)pyridine-3 -sulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -m ethyl ethyl]amino} methyl)phenyl] -6-pyrrolidin-1 -
ylpyridine-3-sulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-3-(2-methyl-l,3-
thiazol-4-yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-5-(3,5-
dimethylisoxazol-4-yl)thiophene-2-sulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino} methyl)phenyl] -4-(5 -methyl-1,3,4-
oxadiazol-2-yl)benzenesulfonamide,
N-[2-({[(lS)-2-cyclohexyl-l-methylethyl]amino}methyl)phenyl]-4-(l,2,4-oxadiazol-3-
yl)benzenesulfonamide,
N- [2-( {[(1 S)-2-cyclohexyl-1 -methylethyl] amino } methyl)phenyl] -3-fluoro-4-( 1Hpyrazol-
1 -yl)benzenesulfonamide,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers,
prodrugs, metabolites, N-oxide or mixtures thereof..
A pharmaceutical composition comprising therapeutically effective amounts of one or
more compounds of claim 1 or 2 together with pharmaceutically acceptable carrier,
excipients or diluents.
A method for treating or preventing a subject suffering from a condition caused by or
contributed to by bacterial infection or fungal infection, comprising administering to the
subject therapeutically effective amounts of one or more compounds of claim 1 or 2 or a
pharmaceutical composition of claim 3.
5. The method according to claim 4 wherein bacterium is selected from Staphylococci,
Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia,
Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium,
Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and the fungal organism
is selected from Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus,
Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces,
Paracoccidiodes, Pneumocystis, Trichophyton or Trichosporium.
6. The method according to claim 4 wherein the condition is selected from community
acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue
infections, hospital acquired lung infections or bone and joint infections, mastitis,
catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
7. A method for the preparation of a compound of Formula 37,
(Figure Removed)
Formula 37
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Xi,X2 and RI are the same as defined in claim 1, D-NH2 is a compound of formula 25,
27, 31,35 and 35b,
(Figure Removed)
which method comprises:
reacting the compound of Formula 5 with a compound of Formula 36
Xl D-NH2
Formula 36
(Figure Removed)
Formulas37
to give a compound of Formula 37.
8. A method for the preparation of a compound of Formula 38,
(Figure Removed)
Formula 38
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Cy, Xi,X2 and RI are the same as defined in claim 1, which method comprises:
reacting the compound of Formula 15 with a compound of Formula 25
NH,
(Figure Removed)
Formula 25
Formula 15
to give a compound of Formula 38.
9. A method for the preparation of a compound of Formulae 43,
Formula 43
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof., wherein:
Cy, X1 and X2 are the same as defined in claim 1; X3 is CH, C(CH3), C(OH) or N; which
method comprises the steps of
(a) protecting the compound of Formula 39
54
to give a compound of Formula 40,
(Figure Removed)
Formula 40
(b) reducing the compound of Formula 40 to give a compound of Formula 41,
(Figure Removed)
Formula 41
(c) reacting the compound of Formula 41 with a compound of Formula 41a
(Figure Removed)
Formula 41a
to give a compound of Formulae 42,
(Figure Removed)
Formula 42
(d) deprotecting the compound of Formula 42 to give a compound of Formula 43.
10. A method for the preparation of a compound of Formula 43a,
(Figure Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
X3 is CH, C(CH3), C(OH) or N; Cy, Xi and X2 are the same as defined in claim 1; which
method comprises the steps of
(a) reacting the compound of Formula 41
Formula 41
with a compound of Formula 41b
Formula 41 b
to give a compound of Formula 42a,
(b) deprotecting the compound of Formula 42a to give a compound of Formula 43a.
11. A method for the preparation of a compound of Formula 46,
(Figure Removed)
Formula 46
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof., wherein:
X3 is CH, C(CH3), C(OH) or N; Rx is methyl, dimethyl amino, 2-thiophenyl or Nmethylimidazolyl;
Cy, Xi and \2 are the same as defined in claim 1; which method
comprises the steps of
(a) reacting the compound of Formula 44 with a compound of formula
to give a compound of Formula 45,
Formula 45
(b) deprotecting the compound of Formula 45 to give a compound of Formula 46.
12. A method for the preparation of a compound of Formula 49,
(Figure Removed)
Formula 49
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Ry is H, 3,5-dimethylisoxazol-4-yl or isoxazol-5-yl; Cy, X\ and
defined earlier; which method comprises the steps of
(a) deprotecting the compound of Formula 40
Cy'
are the same as
(Figure Removed)
Formula 40 NC>2
to give a compound of Formula 47,
Formula 47
(b) reacting the compound of Formula 47 with a compound of formula 47a
Formula 43
to give a compound of Formula 48,
(Figure Removed)
Formula 48
(c) deprotecting the compound of Formula 48 to give a compound of Formula 49.
13. A method for the preparation of a compound of Formula 5 1 ,
FormulaSl N"2
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof., wherein:
Cy, X1 and X2 are the same as defined in claim 1, which method comprises the steps of
(a) reacting the compound of Formula 47
Formula 47
with a compound of formula 41 a
(Figure Removed)
Formula 4 la
to give a compound of Formula 50,
(Figure Removed)
Formula 50
NBoc
NHBoc
(b) deprotecting the compound of Formula 50 to give a compound of Formula 51.
14. A method for the preparation of a compound of Formula 56,
Formula 56
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers,
prodrugs, metabolites, N-oxides or mixtures thereof, wherein:
Cy, Xi and Xa are the same as defined in claim 1, which method comprises the steps of
(a) reacting the compound of Formula 52 with a compound of phenyl chloroformate
BOC x,'
(Figure Removed)
Formula 52 NH2
to give a compound of formula 53
(Figure Removed)
(b) reacting the compound of Formula 53 with a compound of hydrazinehydrate to give a
compound of formula 54, x
(Figure Removed)
Formula 54
O NHNH2
(c) cyclizing the compound of Formula 54 to give a compound of formula 55,
(Figure Removed)
(d) deprotecting the compound of Formula 55 to give a compound of Formula 56.