U.S. patent application number 14/120260 was filed with the patent office on 2014-09-11 for novel nicotine derivatives.
The applicant listed for this patent is Paresh T. Gandhi. Invention is credited to Paresh T. Gandhi.
Application Number | 20140256773 14/120260 |
Document ID | / |
Family ID | 51488552 |
Filed Date | 2014-09-11 |
United States Patent
Application |
20140256773 |
Kind Code |
A1 |
Gandhi; Paresh T. |
September 11, 2014 |
Novel nicotine derivatives
Abstract
Described are novel nicotine derivatives represented by general
formulas (I) and (III), and salts thereof, and herbicide &
pharmaceutical compositions containing the same as the active
ingredient. The compound and salts thereof can control annual or
perennial weed growing on the land where various crops such as rice
plant, wheat, cotton and corn grow for a wide period ranging from
the pre-emergence to growth in a remarkably small dose. The
compounds and salts thereof can be useful as an anti-microbial and
anti-fungal agents and also for the treatment of blood pressure,
skeletal muscle, attention deficit disorder, mental disorders,
schizophrenia, Alzheimer disease, Parkinson's disease and
depression. Also described is the preparation of the nicotine
derivatives having formula (I) and (III).
Inventors: |
Gandhi; Paresh T.; (Totowa,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gandhi; Paresh T. |
Totowa |
NJ |
US |
|
|
Family ID: |
51488552 |
Appl. No.: |
14/120260 |
Filed: |
May 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13694205 |
Nov 7, 2012 |
8754228 |
|
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14120260 |
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61629387 |
Nov 16, 2011 |
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61690461 |
Jun 27, 2012 |
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Current U.S.
Class: |
514/343 |
Current CPC
Class: |
C07D 401/06 20130101;
A01N 43/40 20130101; C07D 409/14 20130101 |
Class at
Publication: |
514/343 |
International
Class: |
C07D 401/06 20060101
C07D401/06; C07D 409/14 20060101 C07D409/14 |
Claims
1. The method for treating a microbial or fungal infection which
comprises administering to a host suffering from such infection an
antimicrobially or antifungally effective amount of a compound of
formula (I), ##STR00037## wherein: X is CH, N or S; n is 0 or 1;
R.sub.1 is hydrogen, acyl, alkyl, halogen, alkoxy, aldehyde,
hydroxy, cyano, nitro, amino, aryl, heteroaryl or heterocyclyl;
R.sub.2 is hydrogen, acyl, alkyl, halogen, alkoxy, aldehyde,
hydroxy, cyano, nitro, amino, aryl, heteroaryl or heterocyclyl; or
salt thereof. R.sub.3 is hydrogen, acyl, alkyl, halogen, alkoxy,
aldehyde, hydroxy, cyano, nitro, amino, aryl, heteroaryl or
heterocyclyl and wherein R.sub.2 and R.sub.3 may be joined together
to form a cycylic ring such as aryl, heteroaryl or
heterocyclic.
2. The method of claim 1, wherein the compound is selected from the
group consisting of:
3-(5-(5-acetylthiophen-2-yl)nicotinoyl)-1-methylpyrrolidin-2-one;
3-(5-(4-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde;
1-methyl-3-(5-m-tolylnicotinoyl)pyrrolidin-2-one;
3-(5-(4-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde;
3-(5-(3-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
3-(5-(4-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
1-methyl-3-(5-p-tolylnicotinoyl)pyrrolidin-2-one;
1-methyl-3-(5-phenylnicotinoyl)pyrrolidin-2-one;
3-(5-(3-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
1-methyl-3-(5-(3-nitrophenyl)nicotinoyl)pyrrolidin-2-one;
3-(5-(2-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
1-methyl-3-(5-o-tolylnicotinoyl)pyrrolidin-2-one;
3-(5-(3,5-dichlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
1-methyl-3-(5-(naphthalen-1-yl)nicotinoyl)pyrrolidin-2-one;
3-(5-(3-acetylphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
3-(5-cyclopropylnicotinoyl)-1-methylpyrrolidin-2-one;
1-methyl-3-(5-(naphthalen-2-yl)nicotinoyl)pyrrolidin-2-one;
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)phenyl
acetate;
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde;
3-(5-(3-hydroxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
3-(5-(2-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one; and
3-(5-(3-aminophenyl)nicotinoyl)-1-methylpyrrolidin-2-one.
3. The method according to claim 1 wherein the infection is a
Mycobacterium tuberculosis infection and the compound administered
comprises:
3-(5-(3,5-dichlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one (ARP
100115)
4. The method according to claim 1 wherein the infection is a
Streptococcus mutans infection and the compound administered is
3-(5-(4-fluorophenyl)nicotinoyl)-1-methylpryrrolidin-2-one
(ARP100102)
5. The method for alleviating pain in a subject which comprises
administering to a host suffering from pain, a pain-relieving
amount of a compound selected from the group consisting of:
4-(5-(1-methyl-2-oxo-pyrrolidin-3-carbonyl)pyridine-3
yl)phenylacetate (ARP100120 and
3-(5-(4-fluorophenyl)nicotinoyl)-1-methylpryrrolidin-2-one
(ARP100102).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of co-pending
U.S. application Ser. No. 13/694,205 filed Nov. 7, 2012 which
claims the benefit of U.S. Provisional Application No. 61/629,387
filed Nov. 16, 2011 and U.S. Provisional Application No. 61/690,461
filed Jun. 27, 2012.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] (Not Applicable)
REFERENCE TO A SEQUENCE LISTING A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISC (SEE 37 CFR
1.52(e)(5)
[0003] (Not Applicable)
FIELD OF THE INVENTION
[0004] The present invention relates to novel nicotine derivatives
represented by general formula (I), salts thereof, and compositions
containing the same as an active ingredient. The compounds and
salts thereof can control annual or perennial weed growing on the
land where various crops such as rice plant, wheat, cotton and corn
grow for a wide period ranging from the pre-emergence to growth in
a remarkably small dose. The compound and salts thereof can be
useful as an anti-microbial & anti-fungal agent, for the
treatment of blood pressure, skeletal muscle, attention deficit
disorder, mental disorders, schizophrenia, Alzheimer's disease
& depression. The present invention also relates to the
preparation of novel nicotine derivatives (formula (I).)
[0005] Nicotine is a well-known ingredient of smoking tobacco and
is known to have deleterious effects when smoked, not the least of
which is its addictive nature. Nicotine has one or more of
insecticidal, pesticidal, anti-microbial, anti-fungal, and
anti-depressant activities. It is believed that the addictive
nature of nicotine is its ability to bind nicotine receptors in the
body.
[0006] The invention thus relates to compounds which have some or
all of the desirable effects of nicotine and lack the full
intensity of the undesirable effects thereof. That is, an object of
the invention is to provide bulky analogues of nicotine which are
too large to bind to the nicotine receptors, yet retain at least to
some extent, the desirable properties mentioned above.
BACKGROUND OF THE INVENTION
[0007] It is already known that nicotine derivatives have
herbicidal activities. For example, nicotine acid derivatives
represented by the formula;
##STR00001##
(Published Specification WO91/10653), heterocyclic derivatives
represented by the formula
##STR00002##
(Published Specification EP0461079) and nicotine acid derivative
represented by the formula
##STR00003##
(Published Specification DE4026177) are known to have herbicidal
activities.
[0008] U.S. Pat. No. 5,877,120 discloses the nicotine acid
derivative having herbicidal activity, which is represented by the
following formula;
##STR00004##
[0009] A number of other herbicides have been developed and
contributed to labor saving in farm work and to the improvement of
the productivity. However, in their practical use, such herbicides
also have various problems with respect to the herbicidal effects
and the safety to crop plants.
[0010] Especially, in cultivation of barley and wheat, few
herbicides can control gramineous weeds congeneric to barley and
wheat, such as water foxtail, black grass and annual blue grass
over a broad period of time from the pre-emergence season to the
growing season of the weeds. Further, few herbicides have a broad
selectivity between these herbicides and barley or wheat.
[0011] The production of agricultural and horticultural crops and
the like is still badly damaged by insect pests and the like, and
the development of a novel agricultural and horticultural chemical,
in particular, agricultural and horticultural insecticide is
desired because of, for example, the appearance of insect pests
resistant to existing chemicals. In addition, because of the
increased population of aged farmers, and the like, various
labor-saving application methods are desired and the development of
an agricultural and horticultural chemical having properties
suitable for the application methods is desired.
[0012] Further, the researchers have been talking about
nicotine-related drugs for decades, but none are on the market yet.
Part of the problem is reputation. Some have suggested that
nicotine drugs be termed "cholinergic-channel modulators" to avoid
the stigma.
[0013] "Nicotine is a pretty promiscuous drug," Dr. Newhouse
explains. "It hits a lot of things at once. But for effective
medications, we want to target specific receptor subtypes." Another
obstacle is that nicotine-related compounds often have a fairly
narrow therapeutic index: There isn't much difference between a
dose that's helpful and one that's toxic. That isn't
insurmountable, but it slows down clinical development.
[0014] Finally, the possibility that nicotine has angiogenic
properties may put a damper on the research. In a review article on
nicotine and angiogenesis published in 2004 in the Annals of
Medicine, researchers John P. Cooke and Haim Bitterman said there
was little reason to be worried about short-term use. In their
opinion, nicotine gums and patches are safe and effective when
"used as directed." But they called on scientists investigating the
therapeutic potential of nicotine-like drugs to take the "potent
angiogenic effects of nicotine" into account. Dr. Newhouse says the
angiogenesis evidence comes largely from animal studies, so it
doesn't necessarily apply to humans. He also points to the good
safety record of the patch and other nicotine replacements, while
noting that there has been some legitimate concern about the
development of insulin resistance.
[0015] In a 2004 Psychopharmacology article, Dr. Newhouse and
Alexandra Potter, Ph.D., reported that the high smoking rate among
adolescents and adults with ADHD could be explained by their
discovery that nicotine improves aspects of their mental
functioning. Potter is recruiting people for two ADHD trials--one
involving nicotine and the other a drug called mecamylamine, which
blocks certain nicotine receptors.
[0016] An especially promising area of research involves cognitive
impairments that are a precursor to Alzheimer's disease. In 2004,
Duke University researchers published a small study on the effect
of the nicotine patch in people with such impairments. They
reported significant improvement in decision-making ability and
attention (but not motor function or memory) in 11 subjects. Those
results led to a larger study funded by the National Institute on
Aging. [0017] Rowland N E et. al. (Psychopharmacology (Berl).
2008-September; 199(4):605-13) discloses that Nicotine analogs with
alpha4beta2 nAChR partial agonist and antagonist efficacies can
inhibit self-administration and may be considered as prototypical
smoking-cessation agents. [0018] Charles S. Pavia (Journal of Med.
Microbiol. Vol 49 (2000), 674-675) discloses that of nicotine has
ability to limit or interfere with growth of selected
micro-organism was a significant finding. [0019] Narang, Rakesh et.
al. discloses that nicotine acid hydrazides derivative has
antimycobacterial, antiviral, antibacterial and antifungal
activities (Letters in Drug Design & Discovery, Volume 8,
Number 8, October 2011, pp. 733-749(17)).
[0020] The present inventor has conducted an extensive research on
nicotine derivatives with the object of developing compounds which
are not phytotoxic to valuable crop plants and have excellent
herbicidal activities and also having good anti microbiological,
anti-fungal activity.
[0021] The present inventor surprisingly found out the nicotine
derivatives, which have good therapeutic effect and useful as
medicament for the treatment of blood pressure, skeletal muscle,
attention deficit disorder, mental disorder, schizophrenia,
Alzheimer disease & depression.
SUMMARY OF THE INVENTION
[0022] In one embodiment, the present invention provides novel
nicotine derivative of general formula (I) or salt thereof,
##STR00005##
wherein:
X is CH, N or S;
[0023] n is 0 or 1; R.sub.1 is hydrogen, alkyl, acyl, halogen,
alkoxy, aldehyde, hydroxy, cyano, nitro, amino, aryl, heteroaryl or
heterocyclyl; R.sub.2 is hydrogen, acyl, alkyl, halogen, alkoxy,
aldehyde, hydroxy, cyano, nitro, amino, aryl, heteroaryl or
heterocyclyl. R.sub.3 is hydrogen, acyl, alkyl, halogen, alkoxy,
aldehyde, hydroxy, cyano, nitro, amino, aryl, heteroaryl or
heterocyclyl and wherein R.sub.2 and R.sub.3 may be joined together
to form a cycylic ring such as aryl, heteroaryl or
heterocyclic.
[0024] In another embodiment, the present invention pertains to the
nicotine acid derivatives set forth in formula (III) below and the
salts thereof.
[0025] In another embodiment, the present invention includes
synthetic intermediates that are useful in preparing the nicotine
derivative of formula (I) and formula (III) and processes for
preparing such intermediates.
[0026] In another embodiment, the present invention relates to the
use of nicotine derivatives of formula (I) and (III) as herbicides,
anti microbial agents, anti fungal agents and gents for the
treatment of blood pressure, skeletal muscle, attention deficit
disorder, mental disorder, schizophrenia, Alzheimer disease,
Parkinson's disease and depression.
[0027] In another embodiment, the present invention relates to
pharmaceutical compositions comprising a nicotine derivative of
formula (I) or (III) as an active ingredient in a pharmaceutically
effective amount, optionally in admixture with diluents, adjuvants
and carriers.
[0028] Another embodiment of the present invention is a method for
preparation of a compound of formula (I) or formula (III) as herein
described. With regard to the compounds of the invention named
herein, it should be noted that the letters (a) through (j) and
(4k) through 4y) appearing after the name of the compound are not
part of the chemical name.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In one embodiment, the present invention provides novel
compounds of general formula (I)
##STR00006##
their salts, wherein R.sub.1, R.sub.2, R.sub.3, X & n are as
defined above.
[0030] A family of specific compounds of particular interest within
the above formula (I) comprises compounds and salts thereof as
follows: [0031]
3-(5-(5-acetylthiophen-2-yl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0032] 3-(5-(4-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0033]
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde;
[0034] 1-methyl-3-(5-m-tolylnicotinoyl)pyrrolidin-2-one; [0035]
3-(5-(4-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one; [0036]
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde;
[0037] 3-(5-(3-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0038] 3-(5-(4-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0039] 1-methyl-3-(5-p-tolylnicotinoyl)pyrrolidin-2-one; [0040]
1-methyl-3-(5-phenylnicotinoyl)pyrrolidin-2-one; [0041]
3-(5-(3-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one; [0042]
1-methyl-3-(5-(3-nitrophenyl)nicotinoyl)pyrrolidin-2-one; [0043]
3-(5-(2-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one; [0044]
1-methyl-3-(5-o-tolylnicotinoyl)pyrrolidin-2-one; [0045]
3-(5-(3,5-dichlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0046] 1-methyl-3-(5-(naphthalen-1-yl)nicotinoyl)pyrrolidin-2-one;
[0047] 3-(5-(3-acetylphenyl)nicotinoyl)-1-methylpyrrolidin-2-one;
[0048] 3-(5-cyclopropylnicotinoyl)-1-methylpyrrolidin-2-one; [0049]
1-methyl-3-(5-(naphthalen-2-yl)nicotinoyl)pyrrolidin-2-one; [0050]
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)phenyl
acetate; [0051]
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehy-
de; [0052]
3-(5-(3-hydroxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one; [0053]
3-(5-(2-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one; [0054]
3-(5-(3-aminophenyl)nicotinoyl)-1-methylpyrrolidin-2-one.
[0055] In another embodiment, the present invention provides novel
nicotine derivative of general formula III or salts thereof,
##STR00007##
wherein: R.sub.o is straight chain alkyl, branched chain alkyl, or
cyclic alkyl or the group
##STR00008##
and n, X, R.sub.1, R.sub.2 and R.sub.3 are as previously described
herein.
[0056] A specific compound of particular interest within general
formula (III) is
3-(5-butylnicotinoyl)-1-methylpyrrolidin-2-one.
DEFINITIONS
[0057] The following definitions apply to the terms as used
throughout this specification, unless otherwise limited in specific
instances:
[0058] The term "derivative" employed herein refers to any compound
encompassed by the generic formula disclosed herein. The derivative
described herein may contain one or more double bonds and
therefore, may exist as isomers, stereoisomers, such as geometric
isomers, E and Z isomers, and may possess asymmetric carbon atoms
(optical centres) and therefore may exist as enantiomers,
diastereoisomers. The derivative may also exist in several
tautomeric forms including the enol form, the keto form and
mixtures thereof. Accordingly, the chemical structures described
herein encompass all possible tautomeric forms of the illustrated
compounds. The nictonic acid derivative described also include
isotopically labeled compounds where one or more atoms have an
atomic mass different from the atomic mass conventionally found in
nature.
[0059] The term "substituted", as used herein, includes mono- and
poly-substitution by a named substituent to the extent such single
and multiple substitution (including multiple substitution at the
same site) is chemically allowed and which means that any one or
more hydrogens on the designated atom is replaced with a selection
from the indicated group, provided that the designated atom's
normal valence is not exceeded, and that the' substitution results
in a stable compound, for example, when a substituent is keto, then
the two hydrogens on the atom are replaced.
[0060] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context.
[0061] The term "salt", as used herein refers to a salt of a
compound, which possesses the desired activity of the parent
compound.
[0062] As used herein, "alkyl" means a saturated hydrocarbon,
including, straight or branched saturated hydrocarbon chains such
as methyl ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
1,1-dimethylethyl, hexyl, octyl, decyl, dodecyl, stearyl, and
saturated hydrocarbon rings, such as cyclopropyl, cyclohexyl and
cyclooctyl, etc.
[0063] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0064] The term "acyl", as used herein, represents a group of
formula --C(.dbd.O)R.sub.b wherein R.sub.b is C.sub.1-6 alkyl,
C.sub.1-6-alkyl hydroxy, C.sub.1-6-alkyl amino or C.sub.1-6-alkyl
aminocarbonyl, as defined herein.
[0065] The term "aldehyde" as used herein, means a group
represented by --CHO.
[0066] As used herein, a "halo" or "halogen" substituent is a
monovalent halogen radical chosen from chloro, bromo, iodo or
fluoro.
[0067] The term "aryl" refers to an aromatic group for example,
which is a 5 to 10 membered monocyclic or bicyclic
carbon-containing ring system, which may be unsubstituted or
substituted.
[0068] The term "heteroaryl" refers to an aromatic group for
example, which is a 3 to 10 membered monocyclic or bicyclic ring
system, which has at least one heteroatom, which may be
unsubstituted or substituted. The term "heteroatom" as used herein
includes oxygen, sulfur and nitrogen.
[0069] The term "heterocyclyl" refers to a fully saturated or
unsaturated nonaromatic cyclic group, for example, which is a 3 to
10 membered monocyclic or bicyclic ring system, which has at least
one heteroatom, which may be unsubstituted or substituted. The term
"heteroatom" as used herein includes oxygen, sulfur and
nitrogen.
[0070] Throughout this specification and the appended claims it is
to be understood that the words "comprise" and "include" and
variations such as "comprises", "comprising", "includes",
"including" are to be interpreted inclusively, unless the context
requires otherwise. That is, the use of these words may imply the
inclusion of an element or elements not specifically recited.
[0071] In another embodiment, present invention provides the
process for preparing the nicotine acid derivative of formula
(I).
[0072] The following reaction schemes are given to disclose the
synthesis of the nicotine acid derivative of formula (I) and other
compounds within formula III according to the present invention.
Accordingly, compounds of the present invention may be prepared as
described in the schemes below using the appropriate variations in
reagents required by the structure of the final compound.
##STR00009##
Step-(a):
[0073] 5-bromonicotine acid (10 g, 49.76 mmol) is alkylated with
alkylating agent like methanol in the presence of concentrated
sulfuric acid at 0.degree. C. under nitrogen atmosphere to obtain
alkyl-5-bromonicotinate.
Step-(b):
[0074] Alkyl-5-bromonicotinate is reacted with pyrrolidine
derivative of formula (VII) represented by below general
formula
##STR00010##
in suitable solvent like toluene, dimethylformamide,
dichloromethane, xylene, dimethylsulofixde in the presence of base
like sodium hydroxide, sodium hydroxide, sodium carbonate, etc at
reflux temperature.
Step-(c):
[0075] A compound of formula (II) is reacted with boronic acid
derivative of formula (VI)
##STR00011##
in the presence of catalyst like
1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II) in
suitable solvent like suitable solvent like toluene,
dimethylformamide, 1,4-dioxane, dichloromethane, xylene,
dimethylsulofixde or mixture thereof in the presence of base like
sodium hydroxide, sodium hydroxide, sodium carbonate under nitrogen
atmosphere.
[0076] The herbicide of the present invention comprises a nicotine
acid derivative of the general formula (I) as an active
ingredient.
[0077] For the compound of the present invention to be used as a
herbicide, the compound of the present invention may be used by
itself. However, it may be used in the form of a formulation such
as a dust, a wettable powder, an emulsifiable concentrate, a
microgranule or a granule by blending it with a carrier, a
surfactant, a dispersant or an adjuvant which is commonly used for
formulations.
[0078] The carrier to be used for such formulations, may, for
example, be a solid carrier such as zeeklite, talc, bentonite,
clay, kaolin, diatomaceous earth, white carbon, vermiculite,
calcium carbonate, slaked lime, siliceous sand, ammonium sulfate or
urea, or a liquid carrier such as isopropyl alcohol, xylene,
cyclohexanone or methylnaphthalene.
[0079] As the surfactant and dispersant, a metal salt of
alkylbenzenesulfonic acid, a metal salt of
dinaphthylmethanedisulfonic acid, a salt of an alcohol sulfuric
acid ester, an alkylaryl sulfonate, a lignin sulfonate, a
polyoxyethylene glycol ether, a polyoxyethylene alkyl aryl ether or
a polyoxyethylene sorbitol monoalkylate may, for example, be
mentioned. The adjuvant may, for example, be carboxymethyl
cellulose, polyethylene glycol or gum arabic. In practical use, the
herbicide may be diluted to a suitable concentration before
application, or may be directly applied.
[0080] The herbicide of the present invention may be used for
application to foliage, soil or water surface. The blending
proportion of the active ingredient is suitably selected as the
case requires. However, in the case of a dust or a granule, the
proportion of the active ingredient is selected suitably within a
range of from 0.01 to 10% by weight, preferably from 0.05 to 5% by
weight. In the case of an emulsifiable concentrate or a wettable
powder, the proportion is selected suitably within a range of from
1 to 50% by weight, preferably from 5 to 30% by weight.
[0081] The dose of the herbicide of the present invention varies
depending upon the type of the compound, the weeds to be
controlled, the germination tendency, the environmental conditions
and the type of the formulation to be used. However, in the case of
a dust or a granule which is used by itself, the dose of the active
ingredient is selected suitably within a range of from 0.1 g to 5
kg, preferably from 1 g to 1 kg, per 10 ares. In the case of an
emulsifiable concentrate or a wettable powder which is used in a
liquid state, the dose of the active ingredient is selected
suitably within a range of from 0.1 to 50,000 ppm, preferably from
10 to 10,000 ppm.
[0082] Further, the compound of the present invention may be used
in combination with an insecticide, a fungicide, another herbicide,
a plant growth controlling agent, a fertilizer or the like, as the
case requires.
[0083] Now, the formulation method will be described with reference
to typical Formulation Examples. The compounds, types of the
additives and blending ratios are not limited to such specific
Examples and may be changed within wide ranges. In the following
description, "parts" means "parts by weight".
[0084] In another embodiment of the invention there is provided a
pharmaceutical composition comprising a therapeutically effective
amount of one or more of a compound of formula (I) or formula
(III). While it is possible to administer therapeutically effective
quantity of compounds of formula (I) either individually or in
combination, directly without any formulation, it is common
practice to administer the compounds in the form of pharmaceutical
dosage forms comprising pharmaceutically acceptable excipient(s)
and at least one active ingredient. These dosage forms may be
administered by a variety of routes including oral, topical,
transdermal, subcutaneous, intramuscular, intravenous, intranasal,
pulmonary etc. Oral compositions may be in the form of solid or
liquid dosage form. Solid dosage form may comprise pellets,
pouches, sachets or discrete units such as tablets,
multi-particulate units, capsules (soft & hard gelatin) etc.
Liquid dosage forms may be in the form of elixirs, suspensions,
emulsions, solutions, syrups etc. Composition intended for oral use
may be prepared according to any method known in the art for the
manufacture of the composition and such pharmaceutical compositions
may contain in addition to active ingredients, excipients such as
diluents, disintegrating agents, binders, solubilizers, lubricants,
glidants, surfactants, suspending agents, emulsifiers, chelating
agents, stabilizers, flavours, sweeteners, colours etc. Some
example of suitable excipients include lactose, cellulose and its
derivatives such as microcrystalline cellulose, methylcellulose,
hydroxy propyl methyl cellulose & ethylcellylose, dicalcium
phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone, various
gums like acacia, tragacanth, xanthan, alginates & its
derivatives, sorbitol, dextrose, xylitol, magnesium Stearate, talc,
colloidal silicon dioxide, mineral oil, glyceryl mono stearate,
glyceryl behenate, sodium starch glycolate, cross povidone,
crosslinked carboxymethylcellulose, various emulsifiers such as
polyethylene glycol, sorbitol, fatty acid esters, polyethylene
glycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl
block copolymers, polyethoxylated fatty acid monoesters, diesters
and mixtures thereof.
[0085] Sterile compositions for injection can be formulated
according to conventional pharmaceutical practice by dissolving or
suspending the active substance in a vehicle such as water for
injection, N-Methyl-2-Pyrrolidone, propylene glycol and other
glycols, alcohols, a naturally occurring vegetable oil like sesame
oil, coconut oil, peanut oil, cotton sead oil or a synthetic fatty
vehicle like ethyl oleate or the like. Buffers, antioxidants,
preservatives, complexing agents like cellulose derivatives,
peptides, polypeptides and cyclodextrins and the like can be
incorporated as required.
[0086] The dosage form can have a slow, delayed or controlled
release of active ingredients in addition to immediate release
dosage forms.
[0087] The amount of active ingredient which is required to achieve
a therapeutic effect will, of course, vary with the particular
compound, the route of administration, the subject under treatment,
and the particular disorder or disease being treated. The compounds
of the invention may be administered orally or parenteraly at a
dose ranging from 0.001 to 1500 mg/kg per day, preferably from 0.01
to 1500 mg/kg per day, more preferably from 0.1 to 1500 mg/kg per
day, most preferably from 0.1 to 500 mg/kg per day. The dose range
for adult humans is generally from 5 mg to 35 g per day and
preferably 5 mg to 2 g per day.
[0088] Tablets or other dosage forms of presentation provided in
discrete units may conveniently contain an amount of compound of
the invention which is effective at such dosage or as a multiple of
the same, for example units containing 1 mg to 1500 mg.
[0089] The processes described in the present invention were
demonstrated in examples illustrated below. These examples are
provided as illustration only and therefore should not be construed
as limitation of the scope of the invention.
EXAMPLES
Example-1
Preparation of methyl 5-bromonicotinate
[0090] A solution of 5-bromonicotine acid (10 g, 49.76 mmol) in 200
ml of methanol was cooled to 0.degree. C. under nitrogen atmosphere
and was added conc.H2SO4 (2.4 ml, 49.76 mmol) slowly drop wise. And
slowly heated to reflux and continued for 15 h, after completion of
the reaction volatiles were removed under reduced pressure. The
resulting solid was dissolved in ethyl acetate (200 ml) and washed
with saturated sodium bicarbonate solution (2.times.50 ml), the
combined organic layer was dried over with sodium sulfate, filtered
and evaporated under reduced pressure to obtain methyl
5-bromonicotinate 2 as an off white solid (9.1 g, 85.1% yield).
[0091] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.12 (s, 1H), 8.84
(s, 1H), 8.43 (s, 1H), 3.96 (s, 3H); Mass (m/z): 216 (M+H)+, 218
(M+2H)+.
Example-2
Preparation of 3-(5-bromonicotinoyl)-1-methylpyrrolidin-2-one
[0092] A suspension of NaH (60% in oil, 1.84 g, 46 mmol) was washed
with toluene (3.times.10 ml) under nitrogen atmosphere. The
resulting slurry in 50 ml of toluene was refluxed for 30 minutes
under nitrogen and to it was added slowly a toluene (25 ml)
solution of methyl 5-bromonicotinate (5 g, 23.26 mmol) and
1-methyl-2-pyrrolidone (4.58 g, 46.5 mmol) for 45 minutes. Then the
reaction mixture was refluxed for 10 h. After completion of the
reaction cooled to room temperature and added 10 ml of saturated
ammonium chloride. The separated organic layer was dried over with
sodium sulfate, filtered and evaporated under reduced pressure to
obtain crude residue which was purified by silica-gel column
chromatography using EtOAc/hexane (60:40) as an eluent to afford an
off white solid (1.6 g, 24.4% yield).
[0093] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.21 (s, 1H), 8.84
(s, 1H), 8.54 (s, 1H), 4.38 (q, 1H), 3.58 (m, 1H), 3.43 (m, 1H),
2.86 (s, 3H), 2.72 (m, 1H), 2.25 (m, 1H); Mass (m/z): 216 (M+H)+,
218 (M+2H)+.
Example-3
Synthesis of Compound Number ARP100101, i.e.,
3-(5-(5-acetylthiophen-2-yl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00012##
[0095] A mixture of 3-(5-bromonicotinoyl)-1-methylpyrrolidin-2-one
3 (1 equiv), 5-Acetyl-2-thiopheneboronic acid (1.2 equiv),
1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex
with DCM (0.1 equiv) and 2M Na2CO3 (4 equiv) in
toluene/1,4-dioxane(4:1, 15 volumes) was degassed and filled with
nitrogen. Then the reaction mixture was heated to 85.degree. C. and
maintained for 2 h. After completion of the reaction filtered
through Celite bed and washed with ethyl acetate. The combined
organic layer was dried over with anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain crude
residue which was purified by silica-gel column chromatography
using 2% MeOH/DCM as an eluent to afford 50% yield of titled
compound.
[0096] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: .quadrature.9.27
(.quadrature..quadrature.s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 7.61
(d, 1H), 7.19 (d, 1H), 4.46 (t, 1H), 3.60 (m, 1H), 3.41 (m, 1H),
2.87 (s, 3H), 2.78 (m, 1H), 2.58 (s, 3H), 2.26 (m, 1H); Mass (m/z):
329.2 (M+H)+
[0097] The following representative compounds of the present
invention were prepared in analogus manner by following the
synthetic routes as described above:
Example-4
Synthesis of Compound Number ARP100102, i.e.,
3-(5-(4-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00013##
[0099] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.26
(.quadrature..quadrature.s, 1H), 8.97 (s, 1H), 8.60 (s, 1H), 7.7
(d, 1H), 7.46 (d, 1H), 4.45 (t, 1H), 3.60 (m, 1H), 3.42 (m, 1H),
2.86 (s, 3H), 2.78 (m, 1H), 2.58 (s, 3H), 2.24 (m, 1H); Mass (m/z):
299.2 (M+H)+.
Example-5
Synthesis of Compound Number ARP100103, i.e.,
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde
##STR00014##
[0101] 1HNMR (500 MHz, CDCl.sub.3): .delta..quadrature. ppm 10.11
(s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.94 (m, 2H),
7.69 (t, 1H), 4.51 (t, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 2.88 (s,
3H), 2.78 (m, 1H), 2.58 (s, 3H), 2.28 (m, 1H); Mass (m/z): 309.2
(M+H)+.
Example-6
Synthesis of Compound Number ARP100104, i.e.,
1-methyl-3-(5-m-tolylnicotinoyl)pyrrolidin-2-one
##STR00015##
[0103] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.26
(.quadrature..quadrature.s, 1H), 9.00 (s, 1H), 8.60 (s, 1H),
7.38-7.42 (m, 3H), 7.22 (s, 1H), 4.49 (t, 1H), 3.61 (m, 1H), 3.44
(m, 1H), 2.88 (s, 3H), 2.74 (m, 1H), 2.44 (s, 3H), 2.28 (m, 1H);
Mass (m/z): 295.2 (M+H)+.
Example-7
Synthesis of Compound Number ARP100105, i.e.,
3-(5-(4-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00016##
[0105] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.15
(.quadrature..quadrature.d, 2H), 8.64 (s, 1H), 7.87 (d, 2H), 7.61
(d, 1H), 4.90 (t, 1H), 3.40-3.43 (m, 2H), 2.74 (s, 3H), 2.21 (s,
2H); Mass (m/z): 315.2 (M+H)+.
Example-8
Synthesis of Compound Number ARP100106, i.e.,
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde
##STR00017##
[0107] 1HNMR (500 MHz, CDCl3): 6 .quadrature. ppm:
.quadrature.10.09 (.quadrature..quadrature.s, 1H), 9.34 (s, 1H),
9.06 (s, 1H), 8.71 (s, 1H), 8.03 (d, 2H), 7.84 (d, 2H), 4.50 (q,
1H), 3.63 (m, 1H), 3.47 (m, 1H), 2.89 (s, 3H), 2.80 (m, 1H), 2.30
(m, 1H); Mass (m/z): 309.2 (M+H)+.
Example-9
Synthesis of Compound Number ARP100107, i.e.,
3-(5-(3-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00018##
[0109] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: .quadrature.9.28
(.quadrature..quadrature.s, 1H), 9.01 (s, 1H), 8.61 (s, 1H), 7.42
(t, 1H), 7.26 (s, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 4.50 (t, 1H),
3.88 (s, 3H), 3.62 (m, 1H), 3.45 (m, 1H), 2.88 (s, 3H), 2.76 (m,
1H), 2.30 (m, 1H); Mass (m/z): 311.2 (M+H)+.
Example-10
Synthesis of Compound Number ARP100108, i.e.,
3-(5-(4-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00019##
[0111] 1HNMR (500 MHz, CDCl.sub.3): .delta..quadrature. ppm:
.quadrature.9.22 (.quadrature..quadrature.s, 1H), 8.98 (s, 1H),
8.59 (s, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 4.48 (t, 1H), 3.87 (s,
3H), 3.62 (m, 1H), 3.42 (m, 1H), 2.88 (s, 3H), 2.78 (m, 1H), 2.26
(m, 1H); Mass (m/z): 311.2 (M+H)+.
Example-11
Synthesis of Compound Number ARP100109, i.e.,
1-methyl-3-(5-p-tolylnicotinoyl)pyrrolidin-2-one
##STR00020##
[0113] 1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: .delta.9.25
(.quadrature..quadrature.s, 1H), 9.00 (s, 1H), 8.61 (s, 1H), 7.53
(d, 2H), 7.31 (d, 2H), 4.5 (t, 1H), 3.63 (m, 1H), 3.46 (m, 1H),
2.89 (s, 3H), 2.77 (m, 1H), 2.42 (s, 3H), 2.28 (m, 1H); Mass (m/z):
295.3 (M+H)+.
Example-12
Synthesis of Compound Number ARP100110 or ARP10010, i.e.,
1-methyl-3-(5-phenylnicotinoyl)pyrrolidin-2-one
##STR00021##
[0115] 1HNMR (500 MHz, CDCl.sub.3): .delta..quadrature. ppm:
.quadrature.9.28 (.quadrature..quadrature.s, 1H), 9.02 (s, 1H),
8.64 (s, 1H), 7.65 (d, 2H), 7.42-7.52 (m, 3H), 4.51 (q, 1H), 3.63
(m, 1H), 3.45 (m, 1H), 2.89 (s, 3H), 2.76 (m, 1H), 2.30 (m, 1H);
Mass (m/z): 281.2 (M+H)+.
Example-13
Synthesis of Compound Number ARP100111, i.e.,
3-(5-(3-fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00022##
[0117] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.29 (s, 1H),
8.96 (s, 1H), 8.61 (s, 1H), 7.46-7.25 (m, 3H), 7.12 (t, 1H), 4.42
(m, 1H), 3.60 (m, 1H), 3.44 (m, 1H), 2.87 (s, 3H), 2.78 (m, 1H),
2.26 (m, 1H); Mass (m/z): 299.3 (M+H).sup.+
Example-14
Synthesis of Compound Number ARP100112, i.e.,
1-methyl-3-(5-(3-nitrophenyl)nicotinoyl)pyrrolidin-2-one
##STR00023##
[0119] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.35 (s, 1H),
9.05 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.30 (d, 1H), 7.96 (d,
1H), 3.61 (m, 1H), 3.42 (m, 1H), 3.35 (m, 1H), 2.87 (s, 3H), 2.28
(m, 1H); Mass (m/z): 326.3 (M+H).sup.+.
Example-15
Synthesis of Compound Number ARP100113, i.e.,
3-(5-(2-methoxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00024##
[0121] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.23 (s, 1H),
8.95 (s, 1H), 8.55 (s, 1H), 7.25-7.36 (m, 2H), 7.05 (m, 2H), 4.47
(m, 1H), 3.82 (s, 3H), 3.60 (m, 1H), 3.42 (m, 1H), 2.87 (s, 3H),
2.70 (m, 1H), 2.15 (m, 1H); Mass (m/z): 311.3 (M+H).sup.+.
Example-16
Synthesis of Compound Number ARP100114, i.e.,
1-methyl-3-(5-o-tolylnicotinoyl)pyrrolidin-2-one
##STR00025##
[0123] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.28 (s, 1H),
8.76 (s, 1H), 8.39 (s, 1H), 7.25-7.31 (m, 4H), 4.46 (q, 1H), 3.62
(m, 1H), 3.42 (m, 1H), 2.87 (s, 3H), 2.74 (m, 1H), 2.30 (s, 3H),
2.28 (m, 1H); Mass (m/z): 295.3 (M+H).sup.+.
Example-17
Synthesis of Compound Number ARP100115, i.e.,
3-(5-(3,5-dichlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00026##
[0125] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.32 (s, 1H),
8.95 (s, 1H), 8.56 (s, 1H), 7.42-7.50 (m, 3H), 4.45 (t, 1H), 3.60
(m, 1H), 3.44 (m, 1H), 2.90 (s, 3H), 2.76 (m, 1H), 2.26 (m, 1H);
Mass (m/z): 349.1 (M+H).sup.+.
Example-18
Synthesis of Compound Number ARP100116, i.e.,
1-methyl-3-(5-(naphthalen-1-yl)nicotinoyl)pyrrolidin-2-one
##STR00027##
[0127] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.37 (s, 1H),
8.93 (s, 1H), 8.54 (s, 1H), 7.93 (d, 2H), 7.80 (d, 2H), 7.40-7.60
(m, 6H), 4.48 (t, 1H), 3.59 (m, 1H), 3.42 (m, 1H), 2.88 (s, 3H),
2.75 (m, 1H), 2.44 (m, 1H), Mass (m/z): 331.2 (M+H).sup.+.
Example-19
Synthesis of Compound Number ARP100117, i.e.,
3-(5-(3-acetylphenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00028##
[0129] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.32 (s, 1H),
9.06 (s, 1H), 8.66 (s, 1H), 8.22 (s, 1H), 8.00 (d, 1H), 7.82 (d,
1H), 7.61 (t, 1H), 4.50 (m, 1H), 3.62 (m, 1H), 3.42 (m, 1H), 2.86
(s, 3H), 2.80 (s, 3H), 2.30 (m, 1H); Mass (m/z): 323.2
(M+H).sup.+.
Example-20
Synthesis of Compound Number ARP100118, i.e.,
3-(5-cyclopropylnicotinoyl)-1-methylpyrrolidin-2-one
##STR00029##
[0131] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.06 (s, 1H),
8.58 (s, 1H), 7.98 (s, 1H), 4.40 (q, 1H), 3.60 (m, 1H), 3.42 (m,
1H), 2.85 (s, 3H), 2.72 (m, 1H), 2.28 (m, 1H); Mass (m/z): 245.1
(M+H).sup.+.
Example-21
Synthesis of Compound Number ARP100119, i.e.,
1-methyl-3-(5-(naphthalen-2-yl)nicotinoyl)pyrrolidin-2-one
##STR00030##
[0133] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.30 (s, 1H),
9.16 (s, 1H), 8.75 (s, 1H), 8.08 (s, 1H), 7.70-7.95 (m, 4H), 7.50
(d, 2H), 4.52 (q, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 2.86 (s, 3H),
2.78 (m, 1H), 2.28 (m, 1H); Mass (m/z): 331.4 (M+H).sup.+.
Example-22
Synthesis of Compound Number ARP100120, i.e.,
4-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)phenyl
acetate
##STR00031##
[0135] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.31 (s, 1H),
9.04 (s, 1H), 8.67 (s, 1H), 8.08 (d, 2H), 7.75 (d, 1H), 4.49 (q,
1H), 3.62 (m, 1H), 3.44 (m, 1H), 2.88 (s, 3H), 2.80 (m, 1H), 2.42
(s, 3H), 2.26 (m, 1H); Mass (m/z): 323.3 (M+H).sup.+.
Example-23
Synthesis of Compound Number ARP100121, i.e.,
3-(5-(1-methyl-2-oxopyrrolidine-3-carbonyl)pyridin-3-yl)benzaldehyde
##STR00032##
[0137] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 10.11 (s,
1H), 9.32 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.94
(m, 2H), 7.68 (d, 1H) 4.49 (t, 1H), 3.61 (m, 1H), 3.44 (m, 1H),
2.86 (s, 3H), 2.76 (m, 1H), 2.44 (s, 3H), 2.28 (m, 1H); Mass (m/z):
309.2 (M+H).sup.+.
Example-24
Synthesis of Compound Number ARP100122, i.e.,
3-(5-butylnicotinoyl)-1-methylpyrrolidin-2-one
##STR00033##
[0139] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.36 (s, 1H),
8.98 (s, 1H), 8.88 (s, 1H), 8.67 (s, 1H), 8.50-8.80 (m, 2H), 4.45
(q, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 3.10 (m, 1H), 2.80-2.95 (m,
5H), 2.30 (m, 1H), 1.70 (m, 2H), 1.42 (m, 2H), 1.00 (t, 3H); Mass
(m/z): 261.3 (M+H).sup.+.
Example-25
Synthesis of Compound Number ARP100123, i.e.,
3-(5-(3-hydroxyphenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00034##
[0141] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.22 (s, 1H),
8.96 (s, 1H), 8.56 (s, 1H), 7.12-7.29 (m, 3H), 6.90 (d, 1H), 4.50
(q, 1H), 3.62 (m, 1H), 3.44 (m, 1H), 2.90 (s, 3H), 2.74 (m, 1H),
2.28 (m, 1H); Mass (m/z): 297.3 (M+H).sup.+.
Example-26
Synthesis of Compound Number ARP100124, i.e.,
3-(5-(2-chlorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00035##
[0143] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.31 (s, 1H),
8.88 (s, 1H), 8.52 (s, 1H), 7.35-7.52 (m, 4H), 4.49 (q, 1H), 3.61
(m, 1H), 3.43 (m, 1H), 2.87 (s, 3H), 2.74 (m, 1H), 2.26 (m, 1H);
Mass (m/z): 315.3 (M+H).sup.+.
Example-27
Synthesis of Compound Number ARP100125, i.e.,
3-(5-(3-aminophenyl)nicotinoyl)-1-methylpyrrolidin-2-one
##STR00036##
[0145] .sup.1HNMR (500 MHz, CDCl.sub.3): .delta. ppm: 9.25 (s, 1H),
9.00 (s, 1H), 8.60 (s, 1H), 7.28 (m, 1H), 7.02 (d, 1H), 6.95 (s,
1H), 6.78 (d, 1H), 4.48 (q, 1H), 3.62 (m, 1H), 3.42 (m, 1H), 2.88
(s, 3H), 2.74 (m, 1H), 2.28 (m, 1H); Mass (m/z): 296.3
(M+H).sup.+.
Correlation of Compound Numbers with Examples
TABLE-US-00001 [0146] Example Compound Number 3 ARP100101 4
ARP100102 5 ARP100103 6 ARP100104 7 ARP100105 8 ARP100106 9
ARP100107 10 ARP100108 11 ARP100109 12 ARP100110 or APR10010 13
ARP100111 14 ARP100112 15 ARP100113 16 ARP100114 17 ARP100115 18
ARP100116 19 ARP100117 20 ARP100118 21 ARP100119 22 ARP100120 23
ARP100121 24 ARP100122 25 ARP100123 26 ARP100124 27 ARP100125
Example 28
[0147] In addition to the other activities displayed, compounds of
the invention variously exhibit anti-fungal and anti-bacterial
activity, anti-amyloid plaque activity, anti-Parkinson's activity
and low blood-brain barrier crossing effect, as measured by
standard molecular docking techniques. The purpose of this example
and Example 29 was to determine in vitro antimicrobial activity of
the test molecules in Gram positive/Gram negative bacteria and
fungi by the disc diffusion method.
The Kirby-Bauer disc diffusion method was used to determine the
antimicrobial activity of test compounds. This is the most commonly
used method for testing in vitro antimicrobial sensitivity.
[0148] Ciprofloxacin, Clindamycin, Amikacin, Flucanozole and
Triclosan were used as standards. (Nictoine was used for
comparative efficacy).
The bacterial cultures Gram positive bacteria (Staphylococcus
aureus, Enterococcus faecalis), Gram negative bacteria (E. Coli and
Pseudomonas aeruginosa) and fungal cultures (Candida albicans &
Cryptococcus neoformans) were used. [0149] a) Preparation of stock
solutions of drugs/compounds. 5000 ug/ml stock solution was
prepared in DMSO for each of the drugs. From this stock solution,
other working stock solutions (100 ug/ml, 50 ug/ml, 25 ug/ml, 5
ug/ml) were prepared by serial dilution. All the working stock
solutions were stored in a refrigerator up to two months. All the
stock solutions were properly labeled. [0150] b) Inoculum
Preparation and Inoculation of Test Plates were done in accordance
with well-known procedures. [0151] c) Interpretation of Results.
After incubation, each plate was examined for the zone of
inhibition. The diameter of the zone of complete inhibition (as
judged by the unaided eye) was measured in mm, including the
diameter of the disc. The diameter of inhibition zone of different
concentrations of the test compound was compared with the
inhibition zones of reference standards in the usual manner. [0152]
d) Conclusion [0153] Based on the results obtained in the above
procedure, it was concluded that compounds ARP100105 and ARP100106
have both antibacterial and antifungal activity. ARP100105 showed
activity at the concentrations of 100 .mu.g and 50 .mu.g and
ARP100106 showed the activity at 100 .mu.g. The compounds ARP100101
(100 .mu.g and 50 .mu.g), ARP100102 (100 .mu.g, 50 .mu.g, 25 .mu.g,
and 5 .mu.g), ARP100104 (100 .mu.g), ARP100108 (100 .mu.g),
ARP100119 (100 .mu.g and 50 .mu.g), ARP100120 (100 .mu.g),
ARP100121 (100 .mu.g and 50 .mu.g) and ARP100122 (100 .mu.g)
exhibit antifungal activity. ARP100111 showed antibacterial
activity at 100 .mu.g on both gram positive and gram negative
bacteria. Nicotine did not show any antibacterial activity at 1000
.mu.g/ml.
Example 29
[0154] Other antibacterial activity has been shown for various
other compounds of the invention. Thus, this example shows the
activity for compound ARP100115 and ARP 100102 against
Mycobacterium Tuberculosis and Streptococcus mutans respectively.
[0155] a) Anti-TB activity using Alamar Blue Dye. [0156] 1) The
anti mycobacterial activity of compounds ARP100102 was assessed
against M. tuberculosis (H37RV Strain) ATCC 25177, using microplate
Alamar Blue assay (MABA) and compound to the reference drugs below.
[0157] 2) This methodology is non-toxic, uses a thermally stable
reagent and shows good correlation with BACTEC radiometric method.
[0158] 3) Briefly, 200 .mu.l of sterile deionized water was added
to all outer perimeter wells of sterile 96 wells plate to minimized
evaporation of medium in the test wells during incubation. [0159]
4) The 96 wells plate received 100 .mu.l of the Middlebrook 7H9
broth and serial dilution of compounds were made directly on plate.
[0160] 5) The final drug concentrations tested were 100 to 0.2
.mu.g/ml. [0161] 6) Plates were covered and sealed with parafilm
and incubated at 37.degree. C. for five days. [0162] 7) After this
time, 25 .mu.l of freshly prepared 1:1 mixture of Almar Blue
reagent and 10% tween 80 was added to the plate and incubated for
24 hours. [0163] 8) A blue color in the well was interpreted as no
bacterial growth, and pink color was scored as growth. [0164] 9)
The MIC was defined as lowest drug concentration which prevented
the color change from blue to pink. Reference drugs minimum
inhibition concentration: [0165] Pyrazinamide--3.125 .mu.g/ml
[0166] Steptomycin--6.25 .mu.g/ml [0167] Ciprofolxacin--3.125
.mu.g/ml The test strain was sensitive to the test compound at
levels down to 0.05 .mu.g/ml, i.e. much lower than the MIC of the
reference drugs shown above. Reference: test employed was: [0168]
Evaluation of anti-Tubercular activity of nicotinic and isoniazid
analogues. ARKIVOC 2007 (xv), 181-191. Maria C. S. Lourenco, Marcus
V. N deSouza, Alessandra C. Pinheiro, Marcelle de L. Ferreira,
Rasnisb B, Goncalves, Thais Cristina M. Nogneira, Monica A.
Peralta. [0169] b) The purpose of this example was to determine the
anti-bacterial activity of compound ARP100102 against Streptococcus
mutans compared to reference drugs. The Kirby Bauer procedure of
Example 28 was followed except that the bacterial culture studied
was Streptococcus mutans and the reference antibiotics were
Ciprofloxacin, Clindamycin, Voncomyzin and Amikacin. When the
diameter of the inhibition zone of the different concentration of
the test compound was compared with the inhibition zones of the
reference standard, the test results showed that Compound ARP100102
showed good antibacterial activity against Streptococcus mutans and
Corynebacterium at 100 .mu.g and 50 .mu.g comparing favorably with
the results obtained on the reference antibiotics at 5 .mu.g to 30
.mu.g concentration. The antibacterial activity of the compound was
better on the Streptococcus mutans organism than on the
Corynebacterium organism. Streptococcus mutans is the bacterium
implicated in the formation of dental curies.
Example 30
[0170] Compounds ARP100102 and ARP100120 demonstrate analgesic
activity as shown in the following tests. [0171] A. The Acetic
Acid-Induced Writhing Response test which causes abdominal
constriction induced by intraperitoneal injection of acetic acid in
the writhing test in mice was carried out according to the method
of Koster et al. Male Albino Mice were divided into the following
groups of six animals each as follows: Experiment: 1. Group-I:
Control-Normal saline (0.1 ml i.p./10 gm) 2. Group-II: Diclofenac
(10 mg/kg body weight, i.p.) 3. Group-V: Compound-ARP100120 (3
mg/kg body weight, i.p.) The number of writhes (abdominal muscular
contractions), stretching of the hind limbs and trunk twisting were
counted 5 minutes after the injection of 1% acetic acid (v/v, 0.1
mL/10 g body weight, i.p.). The data collected represented the
total number of writhes observed in duration of 10 minutes (5-15
minutes after the injection). Percentage inhibition was then
calculated. Percentage inhibition .dbd.(N--N.sup.t/N).times.100,
where N is the average number of writhing of control group and
N.sup.t is the average number of writhing of test group. Results
are as follows:
TABLE-US-00002 [0171] Groups Number of Writhing Percentage
Inhibition Control 47.17 .+-. 4.167 None Diclofenac 34.50 .+-.
1.586* 26.86 ARP100 30.67 .+-. 1.706*** 34.94
[0172] As can be seen, maximum writhing inhibition occurred with
the test compound thus suggesting its use as a peripheral analgesic
on a par with the standard drug diclofenac. [0173] B. The Eddy Hot
Plate method was used to evaluate the CNS analgesic effect of the
test compound. Male Wistar rats initially weighing 180-200 g were
divided into the following groups of six animals each as follows:
Experiment-I: 1. Group-I: Control--10% Dimethyl sulfoxide (DMSO)
(0.5 ml s.c) 2. Group-II: Standard--Pentazocine (20 mg/kg body
weight, s.c.) 3. Group-III: Compound--ARP100102 (0.5 mg/kg body
weight, s.c.) Experiment-II: Same as Experiment I except Group III
dosage was 1 mg/kg body weight. The hot plate method was originally
developed by Woolfe and MacDonald (1944). The paws of rat are very
sensitive to heat at temperatures which are not damaging to the
skin. The response is in the form of jumping, withdrawal of paws or
licking of the paws (Eddy and Leimback, 1953). The animals were
placed on Eddy's hot plate at a temperature of 55.+-.0.5.degree. C.
A cut off period of 20 s, was observed to avoid damage to the paw.
Reaction time and the type of response were noted using a
stopwatch. The latency was recorded before and after 30, 60, 90 and
120 minutes following s.c. injection of test compounds (0.5 mg and
1 mg.kg), standard drug (pentazocine) and control vehicle
respectively. The dose selection of the test compounds was based on
the literature of nicotine (0.32-1.6 mg/kg s.c.). Average reaction
time was then calculated and the percentage variation calculated
using the following ratio:
[0173] Percentage protection=Drug latency-Baseline
latency.times.100 Baseline latency
[0174] The results obtained from the experiments reveal that the
test compound ARP100 showed significant analgesic activity as
compared to the standard drug by significantly increasing the
reaction time in the hot plate test, suggesting its potential as a
central nervous system analgesic.
[0175] Eddy N B, Leimbach D J. J Pharmacol Exptl Therap 1953; 107;
385.
Example 31
Molecular Docking Studies
[0176] Compounds of the invention were evaluated in docking studies
to evaluate the correlation between the compounds and an
art-recognized receptor for a given disease or condition as shown
below.
Molecular docking studies are a well-known device for determining
the ability of a compound under study to react or "dock" with a
receptor site well-known to be responsible for various conditions
or diseases of interest.
[0177] Conformation of the compound under evaluation with the
receptor site as measured by the ability of the compound to "dock"
with the site, and the extent to which it does so, is a measure of
the activity of the compound to alter the biological function of
the receptor site.
[0178] The following known receptors of the indicated conditions
were used in the conformational studies of this Example: [0179] For
Alzheimer's Disease: [0180] Receptor A--acetyl cholinesterase
[0181] Receptor B--N-methyl-D-aspartate (NMDA) [0182] Receptor
C--Butyrylcholinesterase [0183] Receptor E--Beta Secretes for
anti-amyloidal activity [0184] Receptor F--molluscan
acetylcholine-binding protein (ACHBP) [0185] For Alzheimer's
Disease, Schizophrenia, Parkinson's Disease, Depression, ADHD and
Tobacco addiction: [0186] Receptor G--alpha 7 nicotinic
acetylcholine receptor (alpha7nAhR) for memory [0187] For
Serotonin: 5HT4 Receptor [0188] For Parkinson's Disease: [0189]
Receptor D--Metabotropic Glutamate receptor type 4 (mGluR4) [0190]
For Chantix-Like anti-nicotine activity (reduction of nicotine
craving) [0191] Receptor H--10ED [0192] Receptor I--10 LE [0193]
Receptor J--2BG9 [0194] Receptor K--3SQ9 [0195] Receptor
L--IUX2
[0196] Using the foregoing known receptors in docking studies
carried out in accordance with techniques well-known in the art,
activity of the compounds shown below against the relevant
condition, was indicated by the low docking scores of the compounds
of the invention compared to the docking score of the nicotine
control. [0197] Alzheimer's Disease: Compounds ARP100101,
ARP100107, ARP100108, ARP100110, ARP100112, ARP100113, ARP100116,
ARP100117, ARP100119, ARP100120, ARP100123 and ARP100125 [0198]
Parkinson's Disease--ARP100101, ARP100107, ARP100110, ARP100112,
ARP100116, ARP100117, ARP100119, ARP100125 [0199]
Schizophrenia--ARP100110 [0200] Antidepressant--ARP100101 [0201]
ADHD--ARP100110 [0202] Chantix Like--ARP100112, ARP100114,
ARP100116 and ARP100123
[0203] While the invention has been described in detail and with
reference to specific examples thereof, it will be apparent to one
skilled in the art that various changes in modifications can be
made therein without departing from the spirit and scope
thereof.
* * * * *