U.S. patent application number 17/001005 was filed with the patent office on 2021-02-18 for trigonelline based compounds.
The applicant listed for this patent is SPHAERA PHARMA PVT. LTD.. Invention is credited to Sundeep DUGAR, Dinesh MAHAJAN, Somdutta SEN.
Application Number | 20210047269 17/001005 |
Document ID | / |
Family ID | 1000005180981 |
Filed Date | 2021-02-18 |
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United States Patent
Application |
20210047269 |
Kind Code |
A1 |
DUGAR; Sundeep ; et
al. |
February 18, 2021 |
TRIGONELLINE BASED COMPOUNDS
Abstract
The present invention provides novel compounds with improved
solubility and altered pharmacokinetic properties. The compounds of
the present invention may be represented by Formula I as below:
##STR00001##
Inventors: |
DUGAR; Sundeep; (Manesar,
IN) ; MAHAJAN; Dinesh; (Punjab, IN) ; SEN;
Somdutta; (Manesar, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SPHAERA PHARMA PVT. LTD. |
Manesar |
|
IN |
|
|
Family ID: |
1000005180981 |
Appl. No.: |
17/001005 |
Filed: |
August 24, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16085125 |
Sep 14, 2018 |
10752589 |
|
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PCT/IN2017/050091 |
Mar 14, 2017 |
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17001005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/14 20130101;
C07D 401/14 20130101; C07D 213/02 20130101; C07D 213/80 20130101;
C07D 405/12 20130101; C07D 471/14 20130101; A61K 31/337 20130101;
C07D 401/12 20130101; C07D 407/14 20130101 |
International
Class: |
C07D 213/02 20060101
C07D213/02; C07D 401/14 20060101 C07D401/14; C07D 405/14 20060101
C07D405/14; C07D 405/12 20060101 C07D405/12; C07D 471/14 20060101
C07D471/14; C07D 213/80 20060101 C07D213/80; C07D 401/12 20060101
C07D401/12; C07D 407/14 20060101 C07D407/14 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 14, 2016 |
IN |
2882/DEL/2014 |
Claims
1. A compound according to formula I with improved solubility and
altered pharmacokinetic properties ##STR00036## wherein DX- is an
active pharmaceutical ingredient (API) or a drug substance and; X
is either O, or NR; Z is selected from Cl--, Br--, I--, mesylate,
tosylate, tetrafluoroborate, carbonate or phosphate. R is H,
CH.sub.3, lower straight chain or branched chain alkyl,
alternatively X can also be part of a 3-7 membered ring when there
is a bond present between R and another atom on D.
2. The compound of claim 1, wherein the active pharmaceutical
ingredient (API) is selected from the group comprising analgesic
agents; anesthetic agents; antiarthritic agents; respiratory drugs,
including antiasthmatic agents; anticancer agents, including
antineoplastic agents; anticholinergics; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
antihelminthics; antihistamines; antihyperlipidemic agents;
antihypertensive agents; anti-infective agents such as antibiotics
and antiviral agents; antiinflammatory agents; antimigraine
preparations; antinauseants; antiparkinsonism drugs; antipruritics;
antipyretics; antispasmodics; antitubercular agents; antiulcer
agents; antiviral agents; anxiolytics; appetite suppressants;
attention deficit disorder (ADD) and attention deficit
hyperactivity disorder (ADHD) drugs; cardiovascular preparations
including calcium channel blockers, CNS agents; beta-blockers and
antiarrhythmic agents; alpha adrenergic antagonists or agonists;
cough and cold preparations, including decongestants; antitussives;
diuretics; gastrointestinal (GI) motility agents; hormones;
hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive
agents; leukotriene inhibitors; mitotic inhibitors;
phosphodiesterase inhibitors; muscle relaxants; narcotic
antagonists; opiod modulators; nicotine; nictone/acetylcholine
antagonists or agonists; psychostimulants; sedatives; steroids;
tranquilizers; and vasodilators including general coronary,
peripheral and cerebral, preferably selected from the group of
anticancer compounds such as paclitaxel, docetaxel and cabazitaxel;
phosphodiestrase 5 inhibitors such as tadafil; vasodilators such as
dopamine; narcotic antagonists; opiod modulators; nicotine;
nictone/acetylcholine antagonists or agonists; most preferably the
active pharmaceutical ingredient is an anticancer compound.
3. The compound of claim 1, having Formula (II) and Formula (III)
##STR00037##
4. The compound of claim 1, wherein the compound is i.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
iodide; ii.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Mesylate; iii.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Tetrafluoroborate; iv.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Tosylate; v.
3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,-
12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methy-
lpyridin-1-ium iodide; vi.
3-((4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,-
6-trien-1-yl)-2-methoxyphenoxy)carbonyl)-1-methylpyridin-1-ium
iodide; vii.
3,3'-(((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-
-methoxy-4,1-phenylene))bis(oxy))bis(carbonyl))bis(1-methylpyridin-1-ium)
iodide; viii.
3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(ben-
zoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10-
,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-
-yl)oxy)-3-((tert-butoxycarbonyl)amino)-1-oxo-3-phenylpropan-2-yl)oxy)carb-
onyl)-1-methylpyridin-1-ium iodide; ix.
3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-
-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)-1-methylpyridin-1-ium
iodide; x.
3-((((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydro-
xymethyl)tetrahydrofuran-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium
iodide. xi.
3-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)-
piperidine-1-carbonyl)-1-methylpyridin-1-ium; xii.
(R)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)ami-
no)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium;
xiii.
(S)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)ami-
no)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium
iodide
5. The compound of claim 1, having Formula V; ##STR00038## wherein
R.sub.1 is selected from an cyclic or acyclic or branched alkyl,
aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or aralkyl
such as benzyl, hydrogen, tertbutoxycarbonylamino or
N-phenylcarbamoyl; R.sub.2 is selected from hydrogen, hydroxyl,
acyclic, cyclic or branched alkyl, aryl or an aralkyl group;
R.sub.3 and R.sub.4 are independently selected from the group of
hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or
benzyl.
6. A process for the preparation of compound of formula (I) and
intermediates, salts thereof as claimed in claim 1 comprising the
steps of: i) reacting an active pharmaceutical ingredient (API) of
formula D-XHn with nictotine acid derivative of (100) in the
presence of a base and optionally with a catalyst and/or a
dehydrating agent to obtain the compound of (200) ##STR00039##
wherein Y is selected from halides such as F, Cl or Br, and OH and
X is selected from O, N, S or P; and, n=0 to 3 depending on the
valency of X ii) reacting (200) with alkyl halide and optionally
with a catalyst as counter ion to obtain compound of (300)
##STR00040## iii) Optionally, reacting an active pharmaceutical
ingredient (API) of formula D-XHn with
3,3'-(oxybis(carbony))bis(1-methylpyridin-1-ium)iodide to obtain
compound (300); ##STR00041## iv) Optionally, converting the iodine
counter ion of compound (300) to another counter ion by adding a
catalyst and appropriate counter ion to obtain the compound (400);
##STR00042## Wherein M.sup..crclbar. is any counter ion selected
from iodide, chloride, bromide, mesylate, tosylate or tetra
fluoroborate or any other pharmaceutically acceptable anion and the
counterion is either one or more counter ions to balance the
charge.
7. The process as claimed in claim 6, wherein the base used in step
(I) is selected from the group comprising DIPEA (N,
N-Diisopropylethylamine), triethylamine or pyridine, inorganic base
such NaH (sodium hydride) or carbonate salt of sodium or potassium
and the solvent used in step (I) is selected from the group
comprising DCM (dichloromethane), THF (tetrahydrofuran), ACN
(acetonitrile), ethyl acetate etc.
8. The process as claimed in claim 6, wherein the catalyst used in
step (I) is selected from the group comprising DMAP
(4-Dimethylaminopyridine), TBAC (Tert-Butyl Acetate), and the
dehydrating agent used in step (I) is selected from the group
comprising DCC (N,N'-Dicyclohexylcarbodiimide) or EDC
(dichloroethane).
9. The process as claimed in claim 6, wherein the alkyl halide used
in step (I) is selected from the group comprising methyl halide,
methyl chloride, methyl bromide and the catalyst in step (iv) is
selected from the group comprising silver methane sulphonate.
10. The process as claimed in claim 6, wherein the catalyst used in
step (II) is selected from the group comprising 18-crown-6,
12crown-4, DMAP (4-dimethylaminopyridine), TBAC (Tert-Butyl
Acetate).
11. The compound of claim 1, wherein the compound is not a
substrate for CYP450.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel compounds with
improved solubility and altered pharmacokinetic properties and a
method for altering the pharmacokinetic profile of a compound.
BACKGROUND OF THE INVENTION
[0002] Many compounds of pharmaceutical interest face challenges
during the process of drug development because of their
pharmacokinetic or pharmacodynamic properties and also due to their
poor solubility.
[0003] Molecular modifications of a drug substance are designed to
enhance, amongst other aspects, the specificity for a particular
target site, increasing its potency, improving its rate and extent
of absorption, modifying the time span in which the drug becomes
bio-available in the body while preserving the efficacy and
toxicity value of the drug. There are limited number of chemical
modifications known which can enhance aqueous solubility of the
drug substance independent of pH or which can alter the
pharmacokinetic properties of drugs without affecting its efficacy
and toxicity.
[0004] It is interesting to note that, attempts to improve
solubility of pharmaceutical compounds such as taxanes based on
molecular modification have not resulted in any successful clinical
products. Certain prodrugs of Taxol have been prepared which are
purported to undergo in vivo transformation into Taxol and some
other product. For instance, PCT patent publication no. WO
1997044063 discloses certain prodrugs but appears that these
compounds still do not have the desired pharmacokinetic properties.
Pharmaceutical industry majorly depends on novel formulations or
excipients to generate a desirable solubility profile for molecules
of biological interest to develop them for clinical use.
[0005] Some alkaloids having a purine or pyrimidine base type
structures have been known in the prior art for the molecular
modification of drug species for site specific drug delivery. For
instance, EP0110955 B1 discloses a compound of Formula [D-DHC] for
the site specific/sustained delivery of a centrally acting drug
species to the brain. The compound on administration gets converted
to quaternized salt inside the body where it is locked inside the
brain only and the salt entering other parts of the body gets
excreted readily from liver and kidney. Thus, the concentration of
quaternary salt is higher in brain as compared to the other parts
of the body.
[0006] There is still a need to develop better prodrugs or modified
compounds having improved solubility and/or pharmacokinetic
properties for the effective drug delivery without loss of
therapeutic efficacy and increase in toxicity of active molecule or
drug.
OBJECT OF THE INVENTION
[0007] An object of the invention is to provide novel compounds
with better aqueous solubility independent of pH of the media and
improved or altered pharmacokinetic profile by a chemical
modification using trigonelline as derivatizing agent,
SUMMARY OF THE INVENTION
[0008] The present invention provides novel compounds with improved
solubility and altered pharmacokinetic properties. The compounds of
the present invention may be represented by Formula I as below:
##STR00002##
wherein DX- is an active pharmaceutical ingredient (API) or a drug
substance and; X is either O, or NR; or a functionalizable N which
is a part of the API or drug substance. Z is selected from Cl--,
Br--, I--, mesylate, tosylate, tetrafluoroborate, or phosphate.
[0009] R is H, CH.sub.3, lower straight chain or branched chain
alykyl; alternatively X can also be part of a 3-7 membered ring
when there is a bond present between R and another atom on D.
[0010] The present invention also discloses a process of preparing
the compounds of the present invention and use of the compounds of
the present invention and the compound of formula I is not
substrate for CYP450.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Accordingly, the present invention provides a novel compound
with improved solubility and altered pharmacokinetic properties and
a method for altering the pharmacokinetic profile of a
compound.
##STR00003##
wherein DX- is an active pharmaceutical ingredient (API) or a drug
substance and; X is either O, or NR, or a functionalizable N which
is a part of the API or drug substance.
[0012] Z is selected from Cl--, Br--, I--, mesylate, tosylate,
tetrafluoroborate, or phosphate.
[0013] R is H, CH.sub.3, lower straight chain or branched chain
alykyl, alternatively X can also be part of a 3-7 membered ring
when there is a bond present between R and another atom on D.
[0014] The active pharmaceutical ingredient (API) or drug substance
may be selected from the group of analgesic agents; anesthetic
agents; antiarthritic agents; respiratory drugs, including
antiasthmatic agents; anticancer agents, including antineoplastic
agents; anticholinergics; anticonvulsants; antidepressants;
antidiabetic agents; antidiarrheals; antihelminthics;
antihistamines; antihyperlipidemic agents; antihypertensive agents;
anti-infective agents such as antibiotics and antiviral agents;
antiinflammatory agents; antimigraine preparations; antinauseants;
antiparkinsonism drugs; antipruritics; antipyretics;
antispasmodics; antitubercular agents; antiulcer agents; antiviral
agents; anxiolytics; appetite suppressants; attention deficit
disorder (ADD) and attention deficit hyperactivity disorder (ADHD)
drugs; cardiovascular preparations including calcium channel
blockers, CNS agents; beta-blockers and antiarrhythmic agents;
alpha adrenergic antagonists or agonists; cough and cold
preparations, including decongestants; antitussives; diuretics;
gastrointestinal (GI) motility agents; hormones; hormonolytics;
hypnotics; hypoglycemic agents; immunosuppressive agents;
leukotriene inhibitors; mitotic inhibitors; phosphodiesterase
inhibitors; muscle relaxants; narcotic antagonists; opiod
modulators; nicotine; nictone/acetylcholine antagonists or
agonists; psychostimulants; sedatives; steroids; tranquilizers; and
vasodilators including general coronary, peripheral and
cerebral.
[0015] The active pharmaceutical ingredient (API) or drug substance
may preferably be selected from the group of anticancer compounds
such as paclitaxel, docetaxel and cabazitaxel; phosphodiestrase 5
inhibitors such as tadafil; vasodilators such as dopamine; narcotic
antagonists; opiod modulators; nicotine; nictone/acetylcholine
antagonists or agonists; most preferably the active pharmaceutical
ingredient is an anticancer compound.
[0016] The present invention discloses compounds of Formula II and
Formula III;
##STR00004##
[0017] Wherein the drug may be any active pharmaceutical compound
or drug substance as mentioned above.
[0018] The compound of the Formula (II) may be obtained when the
active pharmaceutical ingredient or the drug substance is attached
to the compound of Formula (IV) through a functionalizable oxygen
such as hydroxyl of the active pharmaceutical ingredient or the
drug substance by using standard coupling methods for a hydroxyl
and an acid.
##STR00005##
[0019] The compound of the Formula (III) may be obtained when the
active pharmaceutical ingredient or the drug substance is attached
to the compound of Formula (IV) through a functionalizable nitrogen
such as amino group of the active pharmaceutical ingredient or the
drug substance by using standard coupling methods for a hydroxyl
and an acid.
[0020] The present invention also includes various compounds that
fall within the scope of the compound of formula (I). A compound of
formula I is not substrate for CYP450.
[0021] The compounds of formula (I) are illustrated herein below at
Table 1. Table 1, shows an exemplary but a non-limiting list of
currently existing active pharmaceutical agents or drug substances
that can be modified using the methods described in this
invention.
TABLE-US-00001 TABLE 1 Illustrative compounds of the present
invention Compound no. Structure/Name IUPAC nomenclature 1001
##STR00006## 3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S,
12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11-
dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4,
4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11-
methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)-
oxy)-3-oxo-1-phenylpropan- 2-yl)oxy)carbonyl)-1-
methylpyridin-1-ium iodide 1002 ##STR00007##
3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S,
12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11-
dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4,
4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11-
methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl-
propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Mesylate 1003
##STR00008## 3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S,
12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11-
dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4,
4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11-
methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl-
propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Tetrafluoroborate
1004 ##STR00009## 3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S,
12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11-
dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4,
4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11-
methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl-
propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Tosylate 1005
##STR00010## 3-((6R,12aR)-6-(benzo[d]- [1,3]dioxol-5-yl)-2-methyl-
1,4-dioxo-1,2,3,4,6,7,12, 12a-octahydropyrazino-
[1',2':1,6]pyrido[3,4-b]- indole-7-carbonyl)-1- methylpyridin-1-ium
iodide; 1006 ##STR00011## 3-((4-((1E,4Z,6E)-5-
hydroxy-7-(4-hydroxy- 3-methoxyphenyl)-3- oxohepta-1,4,6-trien-1-
yl)-2-methoxyphenoxy)- carbonyl)-1-methylpyridin- 1-ium iodide 1007
##STR00012## 3,3'-(((((1E,3Z,6E)-3- hydroxy-5-oxohepta-
1,3,6-triene-1,7-diyl)- bis(2-methoxy-4,1- phenylene))bis(oxy))-
bis(carbonyl))bis(1- methylpyridin-1-ium) iodide 1008 ##STR00013##
3-((((2R,3S)-1-(((2aR,4S, 4aS,6R,9S,11S,12S,12aR,
12bS)-12b-acetoxy-12- (benzoyloxy)-4,6,11- trihydroxy-4a,8,13,13-
tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b-
dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)-
oxy)-3-((tert-butoxy- carbonyl)amino)-1-oxo-
3-phenylpropan-2-yl)oxy)- carbonyl)-1-methylpyridin- 1-ium iodide
1009 ##STR00014## 3-((1-((2R,4R,5R)-3,3- difluoro-4-hydroxy-5-
(hydroxymethyl)tetra- hydrofuran-2-yl)-2-oxo-
1,2-dihydropyrimidin-4- yl)carbamoyl)-1-methyl- pyridin-1-ium
iodide 1010 ##STR00015## 3-((((2R,3R,5R)-5-(4-
amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2-
(hydroxymethyl)tetra- hydrofuran-3-yl)oxy)- carbonyl)-1-methyl-
pyridin-1-ium iodide 1011 ##STR00016## 3-((R)-2-((S)-(2,8-bis-
((trifluoromethyl)quinolin- 4 yl)(hydroxy)methyl)-
piperidine-1-carbonyl)-1- methylpyridin-1-ium 1012 ##STR00017##
(R)-3-(((1-(4-((2-(5- chloro-2-fluorophenyl)- 5-isopropylpyrimidin-
4-yl)amino)nicotin- amido)propan-2-yl)oxy)-
carbonyl)-1-methylpyrin- 1-ium 1013 ##STR00018##
(S)-3-(((1-(4-((2-(5- chloro-2-fluorophenyl)-
5-isopropylpyrimidin-4- yl)amino)nicotinamido)-
propan-2-yl)oxy)carbonyl)- 1-methylpyrin-1-ium iodide
[0022] The compounds of the present invention include but are not
limited to: [0023] i.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
iodide; [0024] ii.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Mesylate; [0025] iii.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Tetrafluoroborate; [0026] iv.
3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy--
12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,-
9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]ox-
et-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium
Tosylate; [0027] v.
3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,-
12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methy-
lpyridin-1-ium iodide; [0028] vi.
3-((4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,-
6-trien-1-yl)-2-methoxyphenoxy)carbonyl)-1-methylpyridin-1-ium
iodide; [0029] vii.
3,3'-(((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-meth-
oxy-4,1-phenylene))bis(oxy))bis(carbonyl))bis(1-methylpyridin-1-ium)
iodide; [0030] viii.
3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(ben-
zoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10-
,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-
-yl)oxy)-3-((tert-butoxycarbonyl)amino)-1-oxo-3-phenylpropan-2-yl)oxy)carb-
onyl)-1-methylpyridin-1-ium iodide; [0031] ix.
3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-
-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)-1-methylpyridin-1-ium
iodide; [0032] x.
3-((((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydro-
xymethyl)tetrahydrofuran-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium
iodide. [0033] xi.
3-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4
yl)(hydroxy)methyl) piperidine-1-carbonyl)-1-methylpyridin-1-ium
[0034] xii.
(R)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-y-
l)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium;
[0035] xiii.
(S)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4--
yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium
iodide
[0036] In an aspect, the present invention includes compound of
Formula I, which may be represented by Formula V;
##STR00019##
wherein R.sub.1 is selected from an cyclic or acyclic or branched
alkyl, aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or
aralkyl such as benzyl, hydrogen, tertbutoxycarbonylamino or
N-phenylcarbamoyl; R.sub.2 is selected from hydrogen, hydroxyl,
acyclic, cyclic or branched alkyl, aryl or an aralkyl group;
R.sub.3 and R.sub.4 are independently selected from the group of
hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or
benzyl.
[0037] The present invention also discloses process for preparing
the compound of Formula (I). The compound of Formula (I) may be
prepared by the following general schemes described herein
below:
[0038] The method of preparing the compound of Formula (I) may be
based on the functional group of the active pharmaceutical
ingredient or the drug substance.
[0039] For instance for active pharmaceutical ingredient or the
drug substances containing hydroxyl as the functional group may be
prepared following the synthetic Scheme 1 or 2 as set out herein
below:
General Synthetic Scheme of Modification of Drugs or Molecules of
Biological Interests Having --OH as One of the Functional
Group.
##STR00020##
##STR00021##
[0040] wherein Y is selected from the group comprising OH, Cl, F,
Br or any activated form of acid such as anhydride;
[0041] Wherein the drug may be any active pharmaceutical compound
or drug substance as mentioned above.
[0042] The present invention also discloses a process for synthesis
of compounds of Formula (I), wherein the functional group of the
active ingredient is --NH--.
[0043] For instance, the compounds containing amino group as the
functional group may be prepared the synthetic Scheme 3 or 4 as set
out herein below:
General Synthetic Scheme of Modification of Drugs or Molecules of
Biological Interests Having --NH-- as One of the Functional
Group.
##STR00022##
##STR00023##
[0044] wherein Y is selected from the group comprising OH, Cl, F,
Br or any activated form of acid such as anhydride;
[0045] Wherein the drug may be any active pharmaceutical compound
or drug substance as mentioned above.
[0046] The Synthesis of compounds of Formula I may consist of the
following steps;
Step 1
##STR00024##
[0047] wherein Y is selected from halides such as F, Cl or Br, and
OH and X is selected from O, N, and, n=0 to 2 depending on the
allowable valency of X. The active pharmaceutical ingredient is
dissolved in a solvent and is treated with nicotinic acid or
activated form of nicotinic acid such as nicotinoyl chloride or
corresponding anhydride in presence of a base and optionally with a
catalyst and/or a dehydrating agent at a temperature in the range
of 0 to 60.degree. C.
[0048] The active pharmaceutical ingredient as utilized herein may
be selected from paclitaxel, docetaxel, cabazitaxel, tadafil,
curcumin. The base may be selected from any base such as DIPEA
(N,N-Diisopropylethylamine), triethylamine or pyridine or an
inorganic base such NaH (sodium hydride) or carbonate salt of
sodium or potassium. The solvent may be selected from
dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate,
dimethylformamide etc. The dehydrating agent may be
N,N'-Dicyclohexylcarbodiimide or EDCI etc with or without any
co-catalyst such as dimethylaminopyridine.
Step 2: Synthesis of Compound of Formula I
##STR00025##
[0050] To the product of Step 1 in a suitable solvent is added
alkyl halide such as MeI in stoichiometric or excess amount. The
reaction is then stirred at a temperature in the range of 0.degree.
C. to refluxing for a period until maximum consumption of starting
material. The solvent is removed under vacuum and the residue
obtained is purified with solvent washing or crystallization to
afford purified compound. The solvent may be selected from
acetonitrile, ether, n-pentane, tetrahydrofuran.
[0051] In another embodiment, the process of the present invention
may optionally comprise a co-catalyst such as tetrabutyl ammonium
chloride, or other phase transfer catalyst, for example, quaternary
ammonium salts, quaternary phosphonium salts, polyethylene glycols,
crown ethers, alkyl sulfate salts, and alkyl sulfonates, can be
exemplified amphoteric surfactants and the like, typically,
tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide,
tetrabutylammonium chloride, aliquots 336, hydrogen
trioctylmethylammonium sulfate ammonium, 18-crown-6, tetrabutyl
phosphonium chloride, sodium dodecylsulfate, although lauryl
dimethylamino acetic acid betaine and the like, in addition, also
be used as mixtures of two or more thereof.
Step 3
[0052] Optionally, reacting an active pharmaceutical ingredient
(API) of formula D-XHn with
3,3'-(oxybis(carbony))bis(1-methylpyridin-1-ium)iodide to obtain
compound (300);
##STR00026##
Step 4
[0053] Optionally, converting the iodine counter ion of compound
(300) to another counter ion by adding a catalyst and appropriate
counter ion to obtain the compound (400);
##STR00027##
[0054] Wherein M.sup..crclbar. is any counterion selected from
iodide, chloride, bromide, mesylate, tosylate or tetra fluoroborate
or any other pharmaceutically acceptable anion and the counterion
is either one or more counterions to balance the charge.
[0055] The modified pharmaceutical compounds of the present
invention have enhanced pharmacokinetic properties as compared to
active pharmaceutical ingredient. The modified drugs have more
solubility in wide pH ranges. The modified compounds of the present
invention have a desirable safety and toxicity profile. The
modified compounds of the present invention dissociate into the
pharmaceutical compound and a compound of Formula IV in the
body.
##STR00028##
[0056] Attorney Ref. No. 15985-002US1
[0057] The compound of Formula IV is generically known as
Trigonelline. Trigonelline (N-methylnicotinate) is a pyridine
alkaloid with chemical formula C.sub.7H.sub.7NO.sub.2 mostly
reported from family Fabaceae. It is generally found in the seeds
of the plant, Trigonella foenumgraecum, which is also known as
Fenugreek or Methi. It is a zwitterion formed by the methylation of
the nitrogen atom of niacin (vitamin B.sub.3). It is a
hypocholesterolemic agent and has nutritional benefits and glucose
lowering activity.
[0058] Trigonelline has a GRAS (Generally Recognized as Safe)
status by the FDA. Since it is a naturally occurring metabolite
found in the plants, it is believed that the body is better able to
process the new molecule back into the active, parent drug.
[0059] The modified compounds of this invention are suitable for
use as drugs and/or pharmaceutical agents with improved
pharmacokinetic property, while maintaining a desirable safety and
toxicity profile. The invention also provides a method of
alteration of pharmacokinetic profile of the compounds to render
them more soluble in saline and/or at biologically useful pHs.
[0060] The novel compounds of the present invention may be used for
pharmaceutical and neutraceutical purposes. The compounds of the
present invention are used to treat different types of cancers,
including lymphoma and cancers of the head and neck, breast,
esophagus, lungs, stomach, bladder, prostate, ovarian, melanoma and
other types of solid tumors; Kaposi's sarcoma; in the treatment of
inflammatory disorders such as skin disorders: acne vulgaris,
pulmonary arterial hypertension, anxiety, Alzheimer's disease,
apoptosis; erectile dysfunction; severe hypotension, bradycardia
(slow heart rate), circulatory shock, or cardiac arrest.
[0061] The present invention includes within its scope the salts,
solvates and isomers. Solvates of the compounds of Formula I and
Formula VI are preferably hydrates or any other pharmaceutically
acceptable solvate.
[0062] All stereoisomers of the present compounds, such as those
which may exist due to asymmetric carbons on the active
pharmaceutical ingredient or the drug substance, including
enantiomeric and diastereomeric forms, are contemplated within the
scope of this invention. Individual stereoisomers of the compounds
of the invention may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, selected, stereoisomers. The chiral centers of the present
invention can have the S or R configuration.
[0063] The present invention also envisages within its scope the
effect of selection of suitable counter ions. The counter ion of
the compounds of the present invention may be chosen by selecting
the dissociation constant for the drug capable of ionization within
the said pH range. The counter anions are selected from halides,
mesylates, tosylates, borates, carbonates, phosphates etc.
[0064] The invention thus also provides the use of the modified
entity as defined herein for use in human or veterinary medicine.
The compound for use as a pharmaceutical may be presented as a
pharmaceutical formulation.
[0065] The invention therefore provides in a further aspect a
pharmaceutical formulation comprising the modified compounds of the
invention with a pharmaceutically acceptable carrier thereof and
optionally other therapeutic and/or prophylactic ingredients. The
carriers must be "acceptable" in the sense of being compatible with
the other ingredients of the formula and not deleterious to the
recipient thereof. Suitably the pharmaceutical formulation will be
in an appropriate unit dosage form.
[0066] The pharmaceutical formulations may be any formulation and
include those suitable for oral, intranasal, intraocular or
parenteral (including intramuscular and intravenous)
administration. The formulations may, where appropriate, be
conveniently presented in discrete dosage units and may be prepared
by any of the methods well known in the art of pharmacy. All
methods include the step of bringing into association the active
compound with liquid carriers or finely divided solid carriers or
both, and then, if necessary, shaping the product into the desired
formulation.
[0067] Without being limited by theory, the compounds of the
present invention may not be suitable substrates or inhibitors of
the cytochrome P450 enzymes, such as CYP3A4, enabling reduction in
dose of the active pharmaceutical ingredient or the drug substance
and increasing the safety and efficacy.
[0068] For these purposes the compounds of the present invention
may be administered orally, topically, intranasal, intraocularly,
parenterally, by inhalation spray or rectally in dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles. The term parenteral as
used herein includes subcutaneous injections, intravenous,
intramuscular, intrasteral injection or infusion techniques. In
addition to the treatment of warm-blooded animals such as mice,
rats; horses, dogs, cats, etc., the compounds of the invention are
effective in the treatment of humans.
EXAMPLES
[0069] The following examples are representative of the disclosure,
and provide detailed methods for preparing the compounds of the
disclosure, including the preparation of the intermediate
compounds. The preparation of particular compounds of the
embodiments is described in detail in the following examples, but
the artisan will recognize that the chemical reactions described
may be readily adapted to prepare a number of other agents of the
various embodiments. For example, the synthesis of non-exemplified
compounds may be successfully performed by modifications apparent
to those skilled in the art, e.g. by appropriately protecting
interfering groups, by changing to other suitable reagents known in
the art, or by making routine modifications of reaction
conditions.
[0070] As used herein the symbols and conventions used in these
process, schemes and examples, regardless of whether a particular
abbreviation is specifically defined, are consistent with those
used in the contemporary scientific literature, for example, the
Journal of American Chemical Society or the Journal of Biological
Chemistry.
Example 1: Synthesis of 1001
##STR00029##
[0071] Synthesis of 2'-Nicotinate Ester of Paclitaxel
Step-1
[0072] To a solution of Paclitaxel [1.0 g, 1.1709 mmol, 1.0 mol eq]
in dry DCM 25 ml under nitrogen atmosphere, at 0.degree. C. was
added DIPEA [0.755 g, d=0.756, 5.8527 mmol, 5.0 eq] and the
reaction stirred for 15 min at the same temperature. To the above
reaction was added Nicotinoyl chloride hydrochloride salt [0.625 g,
3.0 eq] all at once, while maintaining the temperature 0.degree. C.
The reaction was stirred at 0.degree. C. for another 30 min and at
RT for 24h. The reaction was worked-up by treating the reaction
mass with 5% aqueous HCl 2.times.20 ml, followed by water
2.times.20 ml, drying over anhydrous Na.sub.2SO.sub.4 and removing
the solvent under vacuum to get the desired product. Yield:
89%.
[0073] MS: ink at 959 and 960,
Step-2
Synthesis of Trigonelline Ester
[0074] To a solution of 2'-Nicotinate ester of Paclitaxel [0.03 g,
0.03125 mmol] in dry ACN 5 ml at RT was added Methyl Iodide in
large excess [0.5 ml]. The reaction was stirred at RT for 24h. ACN
was removed under vacuum and the yellow residue is treated with 1:1
mixture of pentane/diethyl ether 5 ml and triturated to get free
flowing yellow-brown crystals. This process yields the final
product 1001 and yield is -60%.
Examples 2-4: Synthesis of 1002, 1003 and 1004 were Done Exploiting
Procedure of Synthetic Scheme 1 Above
##STR00030##
[0076] MS: ink 974, 975 and 976
[0077] The iodide counterion is converted to the mesylate ion by
adding silver (I) methanesulfonate (1.0 eq) at RT. The reaction
mixture was stirred at RT for 2 h. The reaction was filtered to
remove silver iodide. Filtrate was concentrated under vacuum, which
was triturated with dry ether (2.times.5 ml), ether removed by
decantation and product dried under vacuum to get the desired
product mesylate. This process yields the final product [1002],
[1003], [1004] mesylate as the desired product mesylate.
[0078] The above procedure is used to synthesize a derivative of
curcumin compound (1006) and compound (1007), docetaxel (1008) and
Gemcitabine (1009) and compound (1010) as below:
##STR00031##
Example 5: Synthesis of
3-((6R.12aR)-6-(benzordin.31dioxol-5-yl)-2-methyl-1.4-dioxo-1,2,3,4,6J,12-
.12a-octahydropyrazinori',2':1,61pyridor3,4-blindole-7-carbonyD-1-methylpy-
ridin-1-ium iodide Compound (1005)
Step 1: Synthesis of
(6R,12aR)-6-(benzordin,31dioxol-5-yl)-2-methyl-7-nicotinoyl-hexahydropyra-
zinori',2':1,61pyridor3,4-blindole-1,4-dione
##STR00032##
[0080] To a solution of tadalafil [0.05 g, 0.128 mmol] in dry THF
at 0.degree. C. was added NaH [0.020 g, 0.257 mmol, 2.0 eq] and
reaction stirred until turned to yellow; another portion of NaH
[0.020 g, 0.257 mmol, 2.0 eq] was added followed by addition of
nicotinoyl chloride hydrochloride [0.045, 0.257, 2.0 eq] at
0.degree. C. The reaction was stirred for another 1h at 0.degree.
C. and then at 30.degree. C. for 30 min, followed by addition of
catalytic amounts of 18-crown-6. The reaction was heated to
55.degree. C. (external) and reaction stirred for 36h. The reaction
was poured in water and extracted with ethyl acetate 10
ml.times.2times, dried and ethyl acetate removed under vacuum to
get yellow product. Yield 38 mg. m/z at 494.
Step 2: Synthesis of
3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,-
12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methy-
lpyridin-1-ium iodide
##STR00033##
[0082] To a solution of
6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-7-nicotinoyl-2,3,6,7,12,12-
a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione [0.038
g] in dry ACN at 30.degree. C. was added MeI [0.5 ml]. The reaction
was stirred at the given temperature for 24h. ACN was removed under
vacuum, 1:1 ether:n-pentane added and triturated to get a yellow
precipitate, which was isolated by filtration under suction and
drying. This process yields the final product 1005 and yield is 10
mg. m/z at 509.
Example 6: Synthesis of
33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)pip-
eridine-1-carbonyl)-1-methylpyridin-1-ium iodide (1011)
Step 1: Synthesis of
((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperi-
din-1-yl)(pyridin-3-yl)methanone
##STR00034##
[0084] To a solution of Mefloquine[0.150 g, 0.39 mmol, 1 eq] in DMF
2 ml was added EDC [0.090 g, 0.47 mmol, 1.2 eq] and HOBt [0.069 g,
0.51 mmol, 1.3 eq] then stirred at RT for 20 mins. Now NMM [0.1 ml,
0.79 mmol, 2 eq] and nicotinic acid [0.058 g, 0.47 mmol, 1.2 eq]
then stirred at RT for 24 hr. Ice cold water was slowly added into
the reaction mass, solid so formed was filtered and washed with
cold water and dried over vacuum to obtain
((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl-
)piperidin-1-yl)(pyridin-3-yl)methanone (Yield; 0.100 g, 67%). m/z
at 484
Step 2: Synthesis of
33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)pip-
eridine-1-carbonyl)-1-methylpyridin-1-ium iodide
##STR00035##
[0086] To a solution of
((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperi-
din-1-yl)(pyridin-3-yl)methanone [0.050g] was added MeI [0.1 ml].
The reaction was stirred at the given temperature for 24h. Reaction
mass was evaporated under vacuum, 1:1 ether:n-pentane added and
triturated to get a brown solid
33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)pip-
eridine-1-carbonyl)-1-methylpyridin-1-ium iodide, This process
yields the final product 1011 and yield is 0.035 g, 70%). m/z at
498.
Example 7: Evaluation of Solubility Profile of the Compounds of the
Present Invention
[0087] 1 mg/ml and 2 mg/ml solution of Mefloquine and Tadanafil
respectively and equivalent weight of respective trigonelline
modified compound (1011), compound (1005) of the present invention
was taken in miliQ water, vortexed, centrifuged for 3 min.,
filtered and loaded on HPLC column (Zorbax Eclipse C18; Mobile
Phase: A: 0.1% TFA, B: ACN; run time 15 min, Waters 2996 HPLC
model). Area under the curve for each was determined and based on
that fold increase in solubility was determined. The results are
presented herein below at Table 2.
TABLE-US-00002 TABLE 2 Solubility profile of the compounds of the
present invention Fold increase Concentration in solubility used
for for equiv. wt HPLC of DM using Compound RT Solubility analysis
HPLC Mefloquine 6.92 Poor 1 mg/ml -- solubility 1011 7.03
Completely 1 mg/ml 2.4 fold soluble increase Tadalafil 7.13 Very
poor 2 mg/ml -- solubility 1005 5.93 Completely 2 mg/ml 80 fold
soluble increase
[0088] As shown above in table 2, both modified compound (1011) and
compound (1005) of the present invention showed significant
increase in aqueous solubility over their parent drugs.
Example 8: Solubility of Paclitaxel Modified Drug
[0089] Trigonelline modified drug of Paclitaxel (1001) was
evaluated for its aqueous solubility. Solubility was checked in
different solvent systems. Only those solvents were selected which
were found to solubilize the modified drug at the desirable
concentrations and maintains the stability of the molecule.
Modified drugs were found to be stable in the selected
solvents.
[0090] Solubility of modified drug (1001) was evaluated in normal
saline, 5% DMA in normal saline, 9% NMP in normal saline and 5%
DMSO in normal saline.
[0091] Paclitaxel and compound (1001) presented in the present
invention was taken in different solvent systems mentioned above,
vortexed, centrifuged for 3 min., filtered and loaded on HPLC
column (Zorbax Eclipse C18); Waters 2996 HPLC model). Area under
the curve for each were determined and based on that fold increase
in solubility was determined The results are presented herein below
at Table 3.
TABLE-US-00003 TABLE 3 Solubility results of Paclitaxel and
compound 1001 Solvent 5% DMA 9% NMP 5% DMSO Normal in normal in
Normal in Normal Compound saline saline Saline saline Paclitaxel
0.1 ug/ml Not soluble Not soluble Not soluble 1001 >500 ug/ml ~1
mg/ml >1.5 mg/ml >1.2 mg/ml
[0092] Fold increase in solubility: [0093] >5000.times. in
Normal Saline [0094] >10,000.times. in Normal Saline with 5%
Dimethylacetamide [0095] >12,000.times. in Normal Saline with 5%
Dimethylsulfoxide [0096] 15,000.times. in Normal Saline with 9%
N-Methylpyrrolidone
[0097] From Table 3 above, it can be seen that the compound (1001)
of the present invention demonstrate increased solubility.
Example 9: Comparative PK Profile of Paclitaxel Modified Drug
(1001) with Parent Drug Paclitaxel
[0098] Pharmacokinetics studies were carried out to evaluate the
plasma exposure of modified drug of Paclitaxel in SD rats when
dosed intravenously (IV). The results were compared with exposure
of Paclitaxel using the same dosing vehicle. The dosing vehicle
that was used in this study was PEG400 and Normal saline in fixed
composition. The compound of the present invention (1001) was found
to be stable and soluble in the given solvent. As reported in
solubility data, (1001) displayed better aqueous solubility. This
resulted in easier IV dosing in case of modified drugs. 3 mpk and 1
mpk IV dosing was done for the modified drug and 3 mpk IV for
Paclitaxel parent drug. After IV dosing of the modified drug blood
was collected by serial bleeding at different time points in
heparinized tubes. Blood samples were centrifuged at 10,000 rpm for
5 min. at 4.degree. C. to obtain the plasma, which were aspirated
into separate labeled tubes and stored at -80.degree. C. Extraction
solvent was added to plasma, was vortexed and shaken on shaker for
10 minutes, centrifuged at 10,000 rpm for 10 minutes at 4.degree.
C. Supernatant was kept for analysis.
[0099] Acetonitrile and plasma calibration curves were generated
and percentage of drug recovery from plasma determined.
Quantitative analysis was done by liquid chromatography tandem mass
spectrometer (API3000 LC-MS/MS). Cmax, Tmax, AUC and t1/2 were
calculated using Graph Pad PRISM version 5.04 and the results are
depicted in Table 4
TABLE-US-00004 TABLE 4 Pharmacokinetic profile of the compounds of
the present invention (Paclitaxel) Dose (mg/ Kg, T.sub.1/2
C.sub.max AUC Formulation Compound iv) (hr) (nM) (nM*hr) PEG/Normal
Paclitaxel 3 2.5 104 67 Saline 1001 3* 0.6 8620 874 1001 1* 1.2
2384 301 *3 mpk 1001 = 2.1 mpk Paclitaxel delivered *1 mpk 1001 =
0.71 mpk Paclitaxel delivered
[0100] It can be seen from Table 4 that the modified compound
(1001) of the present invention has more than 80 folds increase in
the Cmax and more than 10 fold increase in the AUC. Hence, the
compound (1001) of the present invention has increased
pharmacokinetic and solubility over the API compounds.
Example 10: Pharmacokinetic Profile of the Compounds (1008) of the
Present Invention (Docetaxel)
[0101] Pharmacokinetics studies were carried out to evaluate the
plasma exposure of modified drug of Docetaxel (1008) in SD rats
when dosed intravenously (IV). The results were compared with
exposure of Docetaxel (10 mpk) using the same dosing vehicle. The
dosing vehicle that was used in this study was PEG400 and Normal
saline in fixed composition. Modified drug of Docetaxel was found
to be stable and soluble in the given solvent.
[0102] Docetaxel modified drug (1008) was found to have
significantly higher exposure as compared to the parent drug as
shown in table
[0103] As reported in solubility data, modified drug of Docetaxel
(1008) displayed better aqueous solubility. 3 mpk IV dosing was
done for the modified drug (1008) and 10 mpk IV for Docetaxel
parent drug. After IV dosing of the modified drug blood was
collected by serial bleeding at different time points in
heparinized tubes. Blood samples were centrifuged at 10,000 rpm for
5 min. at 4.degree. C. to obtain the plasma, which were aspirated
into separate labeled tubes and stored at -80.degree. C. Extraction
solvent was added to plasma, was vortexed and shaken on shaker for
10 minutes, centrifuged at 10,000 rpm for 10 minutes at 4.degree.
C. Supernatant was kept for analysis.
[0104] Acetonitrile and plasma calibration curves were generated
and percentage of drug recovery from plasma determined.
Quantitative analysis was done by liquid chromatography tandem mass
spectrometer (API3000 LC-MS/MS). Cmax, Tmax, AUC and t1/2 were
calculated using Graph Pad PRISM version 5.04 and the results are
depicted in Table 5
TABLE-US-00005 TABLE 5 Pharmacokinetic profile of the compound
(1008) of the present invention Docetaxel Parameters 10 mpk IV 1008
Cmax(nM) 494.96 6924.21 Tmax(hr) 0.08 0.08 AUC(nM*hr) 897.47
1035.34 T.sub.1/2 elimination (hr) 2.06 1.78
[0105] From table 5 above, it can be seen that the compound (1008)
of the present invention has enhanced pharmacokinetics than the
original compound.
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