Specification
DESCRIPTION
Skin property-improving therapeutic agent comprising a
morphinan derivative or any of its pharmacologically
permissible acid addition salts as an active ingredient
Technical Field
[0001]
The present invention relates to the provision of a novel
medicine comprising a morphinan derivative or any of its
pharmacologically permissible acid addition salts useful for
therapy to improve skin properties via a skin moisture
retaining effect.
Background Art
[0002]
It is known that skin roughening, skin drying, skin
darkening, etc. are caused by the functional decline of the
skin barrier, and for the purpose of improving skin
properties, toilet water, foundations, emulsions, horse oil,
ointments, etc. have been being used. As skin property-
improving medicines, medicines for external application
including heparinoids such as Hirudoid, Airleet, Kuradoid,
Seleloiz and Besoften, urea, hyaluronic acid and collagen are
formulated for treating such indications as asteatosis cutis
and keratodermia tylodes palmaris progressiva. Further, it is
also reported that cosmetics comprising, as a main ingredient,
an extract obtained by extracting the roots, subterranean
stems or leaves of Phyllostachys bambusoides, Phyllostachys
nigra or Phyllostachys heterocycle using a hydrophilic organic
solvent (Patent Literature 1) and cosmetics comprising, as a
main ingredient, an extract of bamboo stems or branches
(Patent Literature 2) are effective for improving the dry skin
accompanied by astetic change. It is also reported that some
plant extracts promote the liberation of p-endorphins from
keratinocytes, for promoting the moisture retention of the
skin (Non-Patent Literature 7).
[0003]
In general, in the healthy horny layer of the skin, the
stratum corneum intercellular lipids form a double lipid layer
for retaining water, and since the low molecular water soluble
substances in the keratin cells keep flexibility, the sebum
inhibits percutaneous water transpiration, to keep the skin
surface lubricating. Ceramides play important roles of
retaining skin water and maintaining the barrier function of
the horny layer, and in an alkaline region, it is considered
that ceramidase activity rises to promote the hydrolysis
reactions from ceramides into fatty acids and sphingosine,
resulting in dry skin (Non-Patent Literature 1). About 60% of
the patients treated with hemodialysis are found to suffer
from itching (Non-Patent Literatures 2 and 3) , and on the
other hand, about 90% of them are found to experience dry skin
and to record significant decline in the water content of the
horny layer and significant rise in the pH value of the skin
(Non-Patent Literature 4) . Further, in addition to these,
also in the xeroderma most frequently observed with the
patients treated with hemodialysis, the amount of skin surface
lipids is found to decrease (Non-Patent Literature 5) , and it
is also reported that these patients are higher than healthy
persons in the average pH value of the skin and can have
itching reduced if they are coated with an acid cream having a
lactic acid buffer as an aqueous phase (Non-Patent Literature
6). Skin drying is often accompanied by aging, atopic
dermatitis and the xeroderma occurring especially in winter,
and there is a demand for the development of a moisture
retaining agent that has both the water retaining function and
the barrier function.
[0004]
The morphinan compound used as an active ingredient in
this invention displays opioid k agonism and the applications
of the morphinan compound based on its analgesic activity,
diuretic activity and antitussive activity are already
disclosed (Patent Literature 3) . Further, already disclosed
are applications as brain cell protective (Patent Literature
4), antipruritic agent (Patent Literature 5), hyponatremia
remedy (Patent Literature 6), ORL-1 receptor antagonist
(Patent Literature 7) , remedy for neuropathic pain (Patent
Literature 8), remedy for psychoneurosis (Patent Literature
9), remedy for drug addiction (Patent Literature 10), remedy
for sepsis (Patent Literature 11), antipruritic agent for
pruritus caused by multiple sclerosis (Patent Literature 12),
etc. The Patent Literature 5 discloses the antipruritic
effect by k agonist via the central function.
[0005]
With regard to other opioid-based drugs such as morphine
than those described above, the drugs, the skin improving
effects of which are disclosed, include the following. It is
reported that opioids for external application are effective
for sebaceous gland disorders such as acne and burns (Patent
Literature 13) and that p-endorphine are capable of increasing
the water content of the skin, improving the barrier function
of the skin, promoting the turnover, and preventing the
initial progression of aging (Non-Patent Literature 7) . It
was found in 1999 that p-endorphins exist in the skin, and it
is reported that in vitro, the p-endorphins (1) increase
natural moisturizing factors (amino acids, filaggrin), (2)
increase a turnover regulatory factor (cytokeratin 1), (3)
increase a cell adhesion factor (desmosome), (4) increase the
envelope of the horny layer (involucrin, loricrin), and (5)
increase an anchoring complex (laminin 5). With regard to the
effects of opioids on skin cells, it is reported that P~
endorphins as an agonist enhance the production of cytokeratin
16 as a differentiation marker of epidermis cornification
cells (Non-Patent Literature 8) and that (3-endorphins stimulate
the wandering of keratinocytes (Non-Patent Literature 9).
[0006]
It is known that opioids have analgesic action and on the
other hand also function as a chemical mediator of itching,
and it is reported that endogenous opioid peptides such as P~
endorphins and enkephalins cause itching (Non-Patent
Literature 10). Though details are not clear, it is generally
said that ji-receptors and 5-receptors participate in inhibiting
pain and inducing itching and that K-receptors participate in
inhibiting pain and itching (Non-Patent Literature 11) .
Opioid-based drugs reported to have an antipruritic effect
include naloxone and naltrexone (Non-Patent Literatures 12 and
13) and it is reported that specific morphinan compounds as
active ingredients of the present invention exhibit an
antipruritic effect (Non-Patent Literatures 14, 15 and 16).
Further, among the drugs having (^-receptor blocking activity,
some are reported to be used for therapy such as prevention of
chronic pruritus (Patent Literature 14) and there is a prior
art document concerning the therapy of itching via the action
of inhibiting the peripheral sensory nerves in the skin by
selective inhibition of glutamic acid receptors (Patent
Literature 15).
[0007]
The itching of the skin is defined as "a sense of
inclining to scratch the skin." The dry state of the skin and
the degree of itching generally show a positive correlation,
and it is well known that the improvement of the dry state of
the skin results in the reduction of itching. On the other
hand, there is itching of the skin not accompanied by any
abnormal skin property (Non-Patent Literature 17), and the
relation between central itching and skin properties is not
clear. The central itching caused by excessive reaction with
the itching signals generated by the unbalance of
intracerebral opioid peptides has nothing to do with abnormal
properties of the skin.
[0008]
Therefore, prior art documents do not disclose the skin
property-improving effect of the active ingredient having a
specific morphinan skeleton of this invention at all.
[0009]
[Patent Literature 1] JP5-124930A
[Patent Literature 2] JP7-187990A
[Patent Literature 3] WO93/015081A
[Patent Literature 4] WO95/003307A
[Patent Literature 5] WO98/023290A
[Patent Literature 6] WO99/005146A
[Patent Literature 7] JP2000-53572A
[Patent Literature 8] WO01/014383A
[Patent Literature 9] WO02/078744A
[Patent Literature 10] WO99/011289A
[Patent Literature 11] WO02/089845A
[Patent Literature 12] WO06/095836A
[Patent Literature 13] US Patent No. 5834480
[Patent Literature 14] JP 2004-352714A
[Patent Literature 15] JP2004-107209A
[Non-Patent Literature 1] "Purification and Biochemical
Characterization of Membrane-bound Epidermal Ceramidases from
Guinea Pig Skin," (Yukihiro Yada et al. ) , The Journal of
Biological Chemistry, USA, American Society for Biochemistry
and Molecular Biology, May 26 1995, Vol. 270, No. 21, pages
12677-12684
[Non-Patent Literature 2] "Itching up date: Effectiveness of K-
opioid Agonists for Itching of Dialysis Patients (in
Japanese)," (Hironari Kumagaya et al.), MB Derma, Zen-Ninon
Byoin Shuppan-kai (= Publishing Association of All Japanese
Hospitals), August 25 2005, Vol. 104, pages 59-64
[Non-Patent Literature 3] "Uraemic Pruritus," (Idit F.
Schwartz et al.), Nephrology, Dialysis, Transplantation,
official publication of the European Dialysis and Transplant
Association - European Renal Association, United Kingdom,
Oxford University Press, 1999, Vol, 14, No. 4, pages 834-839
[Non-Patent Literature 4] "Cutaneous Lesions of Dialysis
7
Patients. General Remarks (in Japanese)," (Akira Hattori),
Rinsho Toseki (= Clinical Dialysis), Nihon Medical Center,
October 1995, Vol. 11, No. 13, pages 1877-1881
[Non-Patent Literature 5] "Substances Relating to
Complications Observed with Uremia and Chronic Dialysis X)
Skin Disorders (in Japanese)," (Akira Hattori), Rinsho Toseki
(= Clinical Dialysis), Nihon Medical Center, August 10 2005,
Vol. 21, No. 9, pages 1237-1242
[Non-Patent Literature 6] "Skin Changes in Hemodialysis
Patients (in Japanese)," (Akira Hattori et al.), Rinsho Hifuka
(= Clinical Dermatology), Igaku-Shoin Ltd., January 1990, Vol.
44, No. 1, pages 21-24
[Non-Patent Literature 7] "New Role of p-endorphin in Skin, (in
Japanese)," (Mika Adachi et al.), Fragrance Journal, Fragrance
Journal Ltd., June 15 2005, Vol. 33, No. 6, pages 35-38
[Non-Patent Literature 8] "P-endorphin Stimulates Cytokeratin
16 Expression and Downregulates ji-opiate Receptor Expression in
Human Epidermis," (Mei Bigliardi-Qi et al.), The Journal of
Investigative Dermatology, USA, Nature Publishing Group, March
2000, Vol. 114, No. 3, pages 527-532
[Non-Patent Literature 9] "|u-opiate Receptor and Beta-endorphin
Expression in Nerve Endings and Keratinocytes in Human Skin,"
(Mei Bigliardi-Qi et al.), Dermatology, Switzerland, Karger,
2004, Vol. 209, No. 3, pages 183-189
[Non-Patent Literature 10] "Experimental and Clinical
Pruritus. Studies on Some Putative Peripheral Mediators. The
Influence of Ultraviolet Light and Transcutaneous Nerve
Stimulation," (B. Fjellner), Acta Dermato-venereologica.
Supplementum, Norway, Scandinavian University Press, 1981,
Vol. 97, pages 1-34
[Non-Patent Literature 11] "Opioid Peptide Targetting
Treatment of Pruritus (in Japanese)," (Kenji Takamori), Rinsho
Hifuka (= Clinical Dermatology), Igaku-Shoin Ltd., April 10
2002, Vol. 56, No. 5, pages 145-147
[Non-Patent Literature 12] "Effects of Naltrexone on
Spontaneous Itch-associated Responses in NC Mice with Chronic
Dermatitis," (Tatsuya Maekawa et al.), Japanese Journal of
Pharmacology, The Japanese Pharmacological Society, October 1
2002, Vol. 90, No. 2, pages 193-196
[Non-Patent Literature 13] "Itch-associated Response Induced
by Experimental Dry Skin in Mice," (Takayuki Miyamoto et al.),
Japanese Journal of Pharmacology, The Japanese Pharmacological
Society, March 1 2002, Vol. 88, No. 3, pages 285-292
[Non-Patent Literature 14] "Imbalance in Opioid System as a
Cause of Uremic Pruritus and Effect of a Novel K-Agonist, TRK-
820 (in Japanese)," (Hironari Kumagaya et al.), Sogo Rinsho (=
General Clinical Medicine), Nagai Shoten Co., Ltd., May 1
2004, Vol. 53, No. 5, pages 1678-1684
[Non-Patent Literature 15] "Involvement of Central fj.-opioid
System in the Scratching Behavior in Mice, and the Suppression
of It by the Activation of K-opioid System," (Hideo Umeuchi et
al.), European Journal of Pharmacology, Netherlands, Elsevier
Science, 2003, Vol. 447, No. 1, pages 29-35
[Non-Patent Literature 16] "Anti-Pruritic Effect of a Kappa
Opioid Receptor Agonist TRK-820," (Hideo Umeuchi et al.) ,
Journal of Pharmacological Sciences, The Japanese
Pharmacological Society, March 1 2003, Vol. 91, Supplement No.
1, page 198
[Non-Patent Literature 17] "Knowledge of Diseases Common to
Dermatology Necessary for Surgeons 6. Skin Pruritus and
Mechanism of Itching (in Japanese)," (Shigeo Kochi), Rinsho
Geka (= Clinical Surgery), Igaku-Shoin Ltd., November 20 2001,
Vol. 56, No. 12, pages 1522-1524
Disclosure of the Invention
Problems Which the Invention Tries to Solve
[0010]
The object of this invention is to provide a novel
medicine effective for improving skin properties such as
preventing skin drying, improving skin roughening and
improving the skin darkening involved in hyperkeratosis
(thickened keratin layer) against the decline of the skin
functions brought about by various causes.
Means for Solving the Problems
10
[0011]
The inventors made an intensive study for solving the
abovementioned problems, and as a result, found that a
compound having a specific morphinan skeleton or any of its
pharmacologically permissible acid addition salts is useful as
a skin property-improving therapeutic agent. Thus, this
invention has been completed.
[0012]
This invention relates to the following [1] through [3],
And this invention relates to a method of improving skin
property, comprising administering an effective amount of a
compound as the following [1] through [3].
[1] Skin property-improving therapeutic agent comprising a
compound represented by the following general formula (I):
[Chemical formula 1]
[where the double line consisting of a dotted line and a solid
line denotes a double bond or single bond; R1 denotes a
cycloalkylalkyl with 4 to 7 carbon atoms; R2 denotes a straight
chain or branched alkyl with 1 to 5 carbon atoms; and B
denotes -CH=CH-] or any of its pharmacologically permissible
acid addition salts as an active ingredient.
[2] Skin property-improving therapeutic agent, according to
[1], wherein in the general formula (I), R1 denotes
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or
cyclohexylmethyl; and R2 denotes methyl, ethyl or propyl.
[3] Skin property-improving therapeutic agent, according to
[1], wherein the compound represented by the general formula
(I) is (-)-17-(cyclopropylmethyl)-3,14P~dihydroxy-4,5a-epoxy-
6(3[N-methyl-trans-3- (3-furyl) acrylamide]morphinan.
Effects of the Invention
[0013]
This invention provides a skin property-improving
therapeutic agent comprising a morphinan derivative or any of
its pharmacologically permissible acid addition salts as an
active ingredient. Administration of such a skin property-
improving therapeutic agent can improve skin properties, for
example, can prevent skin drying, improve skin roughening and
improve the skin darkening involved in hyperkeratosis.
Best Modes for Carrying out the Invention
[0014]
The skin property-improving therapeutic agent according
to the present invention comprises as an effective component a
compound represented by the Formula (1) and a pharmaceutically
acceptable acid addition salt thereof:
[0015]
[Chemical formula 2]
(1)
wherein the double line composed of a dashed line and a
solid line represents a double bond or single bond.
[0016]
R1 represents C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C7
cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C4-C7 alkenyl,
allyl, furan-2-yl alkyl (wherein the number of carbon atoms in
the alkyl moiety is 1 to 5) or thiophen-2-yl alkyl (wherein
the number of carbon atoms in the alkyl moiety is 1 to 5).
[0017]
R14 represents hydrogen, hydroxy, nitro, C1-C5 alkanoyloxy,
C1-C5 alkoxy, C1-C5 alkyl, or NR9R10, wherein R9 represents
hydrogen or C1-C5 alkyl; R10 represents hydrogen, C1-C5 alkyl,
or -C=O)Rn, and R11 represents hydrogen, phenyl, or C1-C5
alkyl.
[0018]
R3 represents hydrogen, hydroxy, C1-C5 alkanoyloxy or C1-C5
alkoxy.
A represents -XC(=Y)-, -XC(=Y)Z-, -X- or -XSO2- (wherein
X, Y and Z independently represent NR4, S or 0, wherein R4
represents hydrogen, C1-C5 straight or branched alkyl or C6-C12
aryl, and in cases where more than one R4 are present in the
formula, R4s may be the same or different).
[0019]
B represents valence bond, C1-C14 straight or branched
alkylene (wherein the alkylene may have at least one
substituent selected from the group consisting of C1-C5 alkoxy,
C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine,
iodine, amino, nitro, cyano, trifluoromethyl and phenoxy, and
wherein 1 to 3 methylene groups therein may be replaced with
carbonyl group(s)), C2-C14 straight or branched acyclic
unsaturated hydrocarbon containing 1 to 3 double bonds and/or
triple bonds (wherein the acyclic unsaturated hydrocarbon may
have at least one substituent selected from the group
consisting of C1-C5 alkoxy, C1-C5 alkanoyloxy, hydroxy,
fluorine, chlorine, bromine, iodine, amino, nitro, cyano,
trifluoromethyl and phenoxy, and that 1 to 3 methylene groups
in the acyclic unsaturated hydrocarbon may be replaced with
carbonyl group(s)), or C1-C14 straight or branched saturated or
unsaturated hydrocarbon containing 1 to 5 thioether bonds,
ether bonds and/or amino bonds (wherein a hetero atom does not
directly binds to A, and 1 to 3 methylene groups are
optionally replaced with carbonyl group(s)).
[0020]
14
R5 represents hydrogen or an organic group having a
skeleton selected from those shown below:
[Chemical formula 3]
1 ---T "T" " " ~
Organic groups represented by R5 (wherein Q represents N,
0 or S; T represents CH2, NH, S or 0; 1 represents an integer
of 0 to 5; and m and n independently represent integers of 0
to 5, the total of m and n being not more than 5; each of the
organic groups may have at least one substituent selected from
the group consisting of C1-C5 alkyl, C1-C5 alkoxy, C1-C5
alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine,
amino, nitro, cyano, isothiocyanato, trifluoromethyl,
trifluoromethoxy and methylenedioxy).
[0021]
R6 represents hydrogen; R7 represents hydrogen, hydroxy,
C1-C5 alkoxy or C1-C5 alkanoyloxy; or R6 and R7 together
represent -O-, -CH2- or -S-.
R8 represents hydrogen, C1-C5 alkyl or C1-C5 alkanoyl.
[0022]
R12 and R13 both represent hydrogen, or one of them
represents hydrogen and the other represents hydroxy, or they
together represent oxo.
[0023]
The Formula (1) includes (+), (-) and (±) isomers.]
[0024]
The dashed line in the Formula (1) represents a double
bond or single bond with the latter being preferred.
[0025]
Among the compounds represented by the Formula (1), the
skin property-improving according to the present invention
preferably comprises as an effective component the compound
represented by the already shown Formula (I) or the
pharmaceutically acceptable acid addition salt thereof. The
dashed line in the Formula (I) represents a double bond or
single bond with the latter being preferred.
[0026]
In the formula (I), R1 denotes a cycloalkylalkyl with 4 to
7 carbon atoms. Above all, it is preferred that R1 denotes
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or
cyclohexylmethyl. It is especially preferred that R1 denotes
cyclopropylmethyl.
[0027]
16
R2 denotes a straight chain or branched alkyl with 1 to 5
carbon atoms. It is preferred that R2 denotes methyl, ethyl or
propyl. It is especially preferred that R2 denotes methyl.
[0028]
B denotes -CH=CH-. It is preferred that B denotes trans
form -CH=CH-.
[0029]
It is especially preferred that the compound represented
by the formula (I) is a compound in which R1 denotes
cyclopropylmethyl; R2 denotes methyl; and B denotes trans form
-CH=CH-,namely, (-)-17-(cyclopropylmethyl)-3,14p-dihydroxy-
4, 5
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1289-KOLNP-2010-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf |
2011-10-07 |
| 1 |
1289-KOLNP-2010_EXAMREPORT.pdf |
2016-06-30 |
| 2 |
1289-KOLNP-2010-Correspondence-150515.pdf |
2015-09-07 |
| 2 |
1289-kolnp-2010-specification.pdf |
2011-10-07 |
| 3 |
1289-kolnp-2010-pct request form.pdf |
2011-10-07 |
| 3 |
1289-KOLNP-2010-(15-05-2015)-HEARING SUBMISSION-(ADVANCE COPY).pdf |
2015-05-15 |
| 4 |
1289-kolnp-2010-pct priority document notification.pdf |
2011-10-07 |
| 4 |
1289-KOLNP-2010-(10-10-2014)-ANNEXURE TO FORM 3.pdf |
2014-10-10 |
| 5 |
1289-KOLNP-2010-PCT IPER.pdf |
2011-10-07 |
| 5 |
1289-KOLNP-2010-(10-10-2014)-CORRESPONDENCE.pdf |
2014-10-10 |
| 6 |
1289-KOLNP-2010-PA.pdf |
2011-10-07 |
| 6 |
1289-KOLNP-2010-(10-10-2014)-OTHERS.pdf |
2014-10-10 |
| 7 |
1289-kolnp-2010-others pct form.pdf |
2011-10-07 |
| 7 |
1289-KOLNP-2010-(17-06-2014)-ABSTRACT.pdf |
2014-06-17 |
| 8 |
1289-kolnp-2010-international search report.pdf |
2011-10-07 |
| 8 |
1289-KOLNP-2010-(17-06-2014)-ANNEXURE TO FORM 3.pdf |
2014-06-17 |
| 9 |
1289-KOLNP-2010-(17-06-2014)-CLAIMS.pdf |
2014-06-17 |
| 9 |
1289-kolnp-2010-international publication.pdf |
2011-10-07 |
| 10 |
1289-KOLNP-2010-(17-06-2014)-CORRESPONDENCE.pdf |
2014-06-17 |
| 10 |
1289-kolnp-2010-form 5.pdf |
2011-10-07 |
| 11 |
1289-KOLNP-2010-(17-06-2014)-FORM-1.pdf |
2014-06-17 |
| 11 |
1289-kolnp-2010-form 3.pdf |
2011-10-07 |
| 12 |
1289-KOLNP-2010-(17-06-2014)-FORM-2.pdf |
2014-06-17 |
| 12 |
1289-KOLNP-2010-FORM 3 1.1.pdf |
2011-10-07 |
| 13 |
1289-KOLNP-2010-(17-06-2014)-OTHERS.pdf |
2014-06-17 |
| 13 |
1289-kolnp-2010-form 2.pdf |
2011-10-07 |
| 14 |
1289-KOLNP-2010-(17-06-2014)-PETITION UNDER RULE 137.pdf |
2014-06-17 |
| 14 |
1289-KOLNP-2010-FORM 18.pdf |
2011-10-07 |
| 15 |
1289-KOLNP-2010-(18-06-2013)-ANNEXURE TO FORM 3.pdf |
2013-06-18 |
| 15 |
1289-kolnp-2010-form 1.pdf |
2011-10-07 |
| 16 |
1289-KOLNP-2010-(18-06-2013)-CORRESPONDENCE.pdf |
2013-06-18 |
| 16 |
1289-kolnp-2010-description (complete).pdf |
2011-10-07 |
| 17 |
1289-kolnp-2010-correspondence.pdf |
2011-10-07 |
| 17 |
1289-KOLNP-2010-(18-06-2013)-OTHERS.pdf |
2013-06-18 |
| 18 |
1289-KOLNP-2010-(17-07-2012)-ANNEXURE TO FORM 3.pdf |
2012-07-17 |
| 18 |
1289-KOLNP-2010-CORRESPONDENCE-1.2.pdf |
2011-10-07 |
| 19 |
1289-KOLNP-2010-(17-07-2012)-CORRESPONDENCE.pdf |
2012-07-17 |
| 19 |
1289-KOLNP-2010-CORRESPONDENCE-1.1.pdf |
2011-10-07 |
| 20 |
1289-KOLNP-2010-(17-07-2012)-OTHERS.pdf |
2012-07-17 |
| 20 |
1289-KOLNP-2010-CORRESPONDENCE 1.4.pdf |
2011-10-07 |
| 21 |
1289-KOLNP-2010-(22-11-2011)-CORRESPONDENCE.pdf |
2011-11-22 |
| 21 |
1289-KOLNP-2010-CORRESPONDENCE 1.3.pdf |
2011-10-07 |
| 22 |
1289-KOLNP-2010-(22-11-2011)-OTHERS.pdf |
2011-11-22 |
| 22 |
1289-kolnp-2010-claims.pdf |
2011-10-07 |
| 23 |
1289-KOLNP-2010-(11-11-2011)-AMANDED CLAIMS.pdf |
2011-11-11 |
| 23 |
1289-KOLNP-2010-ASSIGNMENT.pdf |
2011-10-07 |
| 24 |
1289-kolnp-2010-abstract.pdf |
2011-10-07 |
| 24 |
1289-KOLNP-2010-(11-11-2011)-CORRESPONDENCE.pdf |
2011-11-11 |
| 25 |
1289-KOLNP-2010-(11-11-2011)-FORM 13.pdf |
2011-11-11 |
| 26 |
1289-KOLNP-2010-(11-11-2011)-CORRESPONDENCE.pdf |
2011-11-11 |
| 26 |
1289-kolnp-2010-abstract.pdf |
2011-10-07 |
| 27 |
1289-KOLNP-2010-(11-11-2011)-AMANDED CLAIMS.pdf |
2011-11-11 |
| 27 |
1289-KOLNP-2010-ASSIGNMENT.pdf |
2011-10-07 |
| 28 |
1289-KOLNP-2010-(22-11-2011)-OTHERS.pdf |
2011-11-22 |
| 28 |
1289-kolnp-2010-claims.pdf |
2011-10-07 |
| 29 |
1289-KOLNP-2010-(22-11-2011)-CORRESPONDENCE.pdf |
2011-11-22 |
| 29 |
1289-KOLNP-2010-CORRESPONDENCE 1.3.pdf |
2011-10-07 |
| 30 |
1289-KOLNP-2010-(17-07-2012)-OTHERS.pdf |
2012-07-17 |
| 30 |
1289-KOLNP-2010-CORRESPONDENCE 1.4.pdf |
2011-10-07 |
| 31 |
1289-KOLNP-2010-(17-07-2012)-CORRESPONDENCE.pdf |
2012-07-17 |
| 31 |
1289-KOLNP-2010-CORRESPONDENCE-1.1.pdf |
2011-10-07 |
| 32 |
1289-KOLNP-2010-(17-07-2012)-ANNEXURE TO FORM 3.pdf |
2012-07-17 |
| 32 |
1289-KOLNP-2010-CORRESPONDENCE-1.2.pdf |
2011-10-07 |
| 33 |
1289-KOLNP-2010-(18-06-2013)-OTHERS.pdf |
2013-06-18 |
| 33 |
1289-kolnp-2010-correspondence.pdf |
2011-10-07 |
| 34 |
1289-KOLNP-2010-(18-06-2013)-CORRESPONDENCE.pdf |
2013-06-18 |
| 34 |
1289-kolnp-2010-description (complete).pdf |
2011-10-07 |
| 35 |
1289-kolnp-2010-form 1.pdf |
2011-10-07 |
| 35 |
1289-KOLNP-2010-(18-06-2013)-ANNEXURE TO FORM 3.pdf |
2013-06-18 |
| 36 |
1289-KOLNP-2010-FORM 18.pdf |
2011-10-07 |
| 36 |
1289-KOLNP-2010-(17-06-2014)-PETITION UNDER RULE 137.pdf |
2014-06-17 |
| 37 |
1289-KOLNP-2010-(17-06-2014)-OTHERS.pdf |
2014-06-17 |
| 37 |
1289-kolnp-2010-form 2.pdf |
2011-10-07 |
| 38 |
1289-KOLNP-2010-(17-06-2014)-FORM-2.pdf |
2014-06-17 |
| 38 |
1289-KOLNP-2010-FORM 3 1.1.pdf |
2011-10-07 |
| 39 |
1289-KOLNP-2010-(17-06-2014)-FORM-1.pdf |
2014-06-17 |
| 39 |
1289-kolnp-2010-form 3.pdf |
2011-10-07 |
| 40 |
1289-KOLNP-2010-(17-06-2014)-CORRESPONDENCE.pdf |
2014-06-17 |
| 40 |
1289-kolnp-2010-form 5.pdf |
2011-10-07 |
| 41 |
1289-KOLNP-2010-(17-06-2014)-CLAIMS.pdf |
2014-06-17 |
| 41 |
1289-kolnp-2010-international publication.pdf |
2011-10-07 |
| 42 |
1289-KOLNP-2010-(17-06-2014)-ANNEXURE TO FORM 3.pdf |
2014-06-17 |
| 42 |
1289-kolnp-2010-international search report.pdf |
2011-10-07 |
| 43 |
1289-KOLNP-2010-(17-06-2014)-ABSTRACT.pdf |
2014-06-17 |
| 43 |
1289-kolnp-2010-others pct form.pdf |
2011-10-07 |
| 44 |
1289-KOLNP-2010-(10-10-2014)-OTHERS.pdf |
2014-10-10 |
| 44 |
1289-KOLNP-2010-PA.pdf |
2011-10-07 |
| 45 |
1289-KOLNP-2010-(10-10-2014)-CORRESPONDENCE.pdf |
2014-10-10 |
| 45 |
1289-KOLNP-2010-PCT IPER.pdf |
2011-10-07 |
| 46 |
1289-kolnp-2010-pct priority document notification.pdf |
2011-10-07 |
| 46 |
1289-KOLNP-2010-(10-10-2014)-ANNEXURE TO FORM 3.pdf |
2014-10-10 |
| 47 |
1289-kolnp-2010-pct request form.pdf |
2011-10-07 |
| 47 |
1289-KOLNP-2010-(15-05-2015)-HEARING SUBMISSION-(ADVANCE COPY).pdf |
2015-05-15 |
| 48 |
1289-kolnp-2010-specification.pdf |
2011-10-07 |
| 48 |
1289-KOLNP-2010-Correspondence-150515.pdf |
2015-09-07 |
| 49 |
1289-KOLNP-2010_EXAMREPORT.pdf |
2016-06-30 |
| 49 |
1289-KOLNP-2010-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf |
2011-10-07 |