Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-03-13
2002-10-01
Ramser, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C558S419000
Reexamination Certificate
active
06458835
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for inhibiting hair loss and/or promoting hair growth in chemotherapy patients employing the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile or pharmaceutical compositions containing same.
BACKGROUND OF THE INVENTION
Potassium channel openers such as minoxidil (Upjohn), pinacidil (Lilly) and diazoxide (Shiseido and Schering-Plough) are known for their hair growth stimulating activity. Thus, U.S. Pat. Nos. 4,596,812 and 4,139,619 disclose use of minoxidil in the treatment of male pattern baldness, alopecia areata and balding in females. U.S. Pat. No. 4,057,636 discloses pinacidil. DE 3,827,467A discloses combinations of minoxidil and hydrocortisone or retinoids.
U.S. Pat. No. 5,011,837 to Atwal et al discloses aryl cyanoguanidines which possess potassium channel activating activity and are useful therapy for hypertension and other cardiovascular disorders, for various central nervous system disorders, kidney and urinary problems as well as for the promotion of hair growth, for example in the treatment of male pattern baldness (alopecia). These aryl cyanoguanidines have the structure
and its possible tautomers
and
including pharmaceutically acceptable salts, wherein
R
1
is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl;
R
2
is
R
3
and R
4
are each independently selected form −R
2
, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halo, alkoxy, —NHalkyl, —N-(alkyl)
2
, —S-alkyl, —O-aryl-alkyl, —S-arylalkyl or —S-aryl, —O-aryl, —NHaryl-alkyl, or R
2
and R
3
taken together are a group which form a ring with the two carbon atoms to which they are attached, which group is selected from
wherein
m=1 or 2,
n=3-5,
p=2-4,
X is 0, NR
5
, CH
2
; and
R
5
is hydrogen or R
1
.
Example 1 of U.S. Pat. No. 5,011,837 discloses the preparation of 4-[[(cyanoimino)-[(1,2,2-trimethylpropyl)amino]benzonitrile
in the form of its racemic mixture.
U.S. Pat. No. 6,013,668 discloses a method for promoting hair growth in humans employing the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)-amino]methyl]amino]benzonitrile.
PCT Application WO 92/02225 discloses a combination of a potassium channel opener and a 5-&agr;-reductase inhibitor for promoting hair growth.
PCT Application WO 92/09259A discloses use of an androgen blocker and a potassium channel activator for stimulation of hair growth.
PCT Application WO 96/29988 discloses a topical formulation containing minoxide or minoxidil in combination with a testosterone 5-&agr; reductase inhibitor.
PCT Application WO 94/18936 discloses a method for promoting hair growth employing a vasodilator such as minoxidil in combination with estradiol and/or a 5-&agr;-reductase inhibitor.
The use of minoxidil in cancer patients to decrease the duration of baldness caused by chemotherapy is disclosed by Duvic, M. et al, “A randomized trial of minoxidil in chemotherapy-induced alopecia”, J. Am. Acad Dermalol 1996; 35:74-8. Duvic et al disclose that in patients treated with fluorouracil, doxorubicin and cyclophosphamide a 2% topical solution of minoxdil administered during chemotherapy and 4 weeks thereafter, did not prevent alopecia but did decrease period of baldness.
Rodriguez, R. et al “Minoxidil (Mx) as a prophylaxis of doxorubicin-induced alopecia”, Annals of Oncology 5:769-770, 1994 discloses that a 2% topical solution of minoxidil was not effective in preventing doxorubicin-induced alopecia.
Hussein, A. M., “Protection Against Cytosine Arabinoside-Induced Alopecia By Minoxidil In A Rat Animal Model”, Int. J. Dermatol. Vol. 34(7); 470-3, 1995 discloses that minoxidil, when injected locally, offered good local prevention against 1-B-D-arabinofurano-sylcytosine but not cyclophosphamide-induced alopecia.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a method is provided for preventing or inhibiting chemotherapy-induced or radiation therapy-induced hair loss wherein a therapeutically effective amount of the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)-amino]methyl]amino]benzonitrile, (hereinafter “the (R)-enantiomer”) is administered to a human or other mammal.
In addition, in accordance with the present invention, a method is provided for promoting hair growth in a patient undergoing chemotherapy or radiation and/or having chemotherapy-induced hair loss or radiation-induced hair loss, wherein a therapeutically effective amount of the (R)-enantiomer is administered to the patient.
In carrying out the above methods, the (R)-enantiomer will be administered to the patient prior to and/or simultaneously with and/or subsequent to chemotherapy and/or radiation therapy.
The above (R)-enantiomer of the invention has the structure I
The (R)-enantiomer will preferably be in substantially pure form, that is, will be at least 99% pure (R)-enantiomer and will at most contain 1% (S)-enantiomer.
The method of the present invention also includes the use of pharmaceutical compositions containing the (R)-enantiomer and a pharmaceutically acceptable carrier therefor.
The (R)-enantiomer may be prepared as described in U.S. Pat. No. 6,013,668 which is incorporated herein by reference.
The (R)-enantiomer may be administered by itself or may be administered prior to, simultaneous with or after the antineoplastic agent used in chemotherapy, or prior to simultaneously with or after radiation therapy. In a preferred embodiment of the present invention, the (R)-enantiomer is administered prior to the antineoplastic agent or radiation therapy.
As used herein, the term “simultaneous” means that the antineoplastic agent or radiation therapy and the (R)-enantiomer are administered within 24 hours, preferably 12 hours, more preferably 6 hours, and most preferably 3 hours, of each other.
The chemotherapeutic agent which may be employed with the (R)-enantiomer may include any of the antineoplastic agents listed in the Physician's Desk Reference.
As used herein, the phrase “radiation therapy” includes, but is not limited to, x-rays or gamma rays which are delivered from either an externally applied source such as a beam or by implantation of small radioactive sources.
As used herein, the phrase “antineoplastic agent” refers to compounds which prevent cancer cells from multiplying. In general, the antineoplastic agents of this invention prevent cancer cells from multiplying by: (1) interfering with the cell's ability to replicate DNA, or (2) inducing apoptosis in the cancerous cells.
Examples of antineoplastic agents which are suitable for use in the methods of this invention include, but are not limited to, microtuble-stabilizing agents such as the taxanes, for example, paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), 7-O-methylthio-methylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176), 3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in U.S. Ser. No. 60/179,965 filed on Feb. 3, 2000, and example 17 herein), C-4 methyl carbonate paclitaxel (disclosed in WO 94/14787), the epothilone, such as epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione (disclosed in WO 99/02514), [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-di-hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabi-cyclo[14.1.0]-heptadecane-5,9-dione (disclosed in U.S. Ser. No. 09/506,481 filed on Feb. 17, 2000, and examples 7 and 8 herein), and derivatives thereof; microtuble-disruptor agents; alkylating agents; anti-metabolites; epidophy
Bristol--Myers Squibb Company
Ramser Robert W.
Rodney Burton
Sackey Ebenezer
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