MXPA00001069A - Enantiomers of 4-[[(cyanoimino)- [(1,2,2-trimethylpropyl) amino]methyl]amino]benzonitrile - Google Patents

Abstract

4-[[(cyanoimino)- [(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile as well as the corresponding (S)-enantiomerare useful for promoting hair growth such as in male pattern baldness.

Description

ENANTIOMEROS DE 4 - [[(CIANOIMINO) [1, 2, 2 - TRIMETHYLPROPIL) AMINO) ME IL] AMINO] BENZONI RILO FIELD OF THE INVENTION The present invention relates to the (R) and (S) enantiomers of 4- [[(cyanoimino) [1,2,2-trimethylpropyl) to ino) methyl] amino] benzonitrile, to pharmaceutical compositions containing the same, a method to promote hair growth using those enantiomers.

BACKGROUND OF THE INVENTION Openers of potassium channels, such as minoxidil (Upjohn), pinacidil (Lilly) and diazoxide (Shisheido and Schering-Plow) are known for their hair growth stimulating activity. Thus, US Patent Nos. 4,596,812 and 4,139,619 describe the use of minoxidil in the treatment of male pattern baldness, alopecia areata and baldness in women. U.S. Patent No. 4,057,636 describes the REF. : 32441 pinacidil DE 3,827,467A describes combinations of minoxidil and hydr ocor t i sona or retino ides. US Patent No. 5,011,837 issued to At al et al discloses aryl anoguanidines having potassium channel activating activity and are useful for the therapy of hypertension and other cardiovascular disorders, for various central nervous system disorders, for urinary and kidney 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 including the pharmaceutically acceptable salts, wherein Ri is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, arylalkyl or cycloalkyl-chyle; R is O or o -Cas, - K? 2, - cRj, - c- C s, - C - a? No, O 11 'amino.substituted, -cr3 or -S- i R3 and R4 are each independently selected from -R2, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halo, alkoxy, -NHalkyl, -N- (al qui 1) 2 / -S-alkyl, -O-aryl -alkyl, - S-ar i 1 to which o-S-aryl, -O-aryl, NHaryl-alkyi, or R 2 and R 3 taken together are a group that forms a ring with the two carbon atoms to which they are attached. united, and the group is selected from -S- (CS2) a -CH2-, -CZ (CH2) pCH2-, - C-CH3 (CH2) p > -; where = 1 or 2, n = 3-5 P = 2-4, X is 0, NR5, CH2; and Rs is hydrogen or Ri The example 1 - of the patent No. 5,011,837 describes the preparation of 4 - [[cyano] i) - [(1,2, 2-trimethylpropyl) amino] benzonitrile in the form of its racemic mixture. PCT application WO 92/02225 discloses a combination of a potassium channel opener and a 5-a-r educt asa inhibitor to promote hair growth. PCT application WO 92/09259A describes the use of an androgen blocker and a potassium channel activator to stimulate hair growth.

DESCRIPTION OF THE INVENTION In accordance with the present invention, it has unexpectedly been found that the (R) -enantiomer of 4-. { [cyanoimino) [(1,2,2-trimethylpropyl) amino] -methyl] amino] benzonitrile, including the pharmaceutically acceptable salts thereof, exhibits a remarkable hair growth promoting activity which is superior in that respect to that of the enantiomer (S) and the racemic mixture of these enantiomers. Indeed, it has been found that the (R) enantiomer is, surprisingly and unexpectedly, more effective in stimulating hair follicles, to produce hair growth at a substantially higher rate when compared to the corresponding (S) enantiomer. . The above (R) enantiomer of the invention has the structure I The (R) I enantiomer will be substantially in pure form, ie, it will be at least the (R) 99% pure enantiomer and will contain at most 1% of the (S) enantiomer. Further, in accordance with the present invention, it has been found that the (S) enantiomer of 4- [[(cyanoimino) - [(1,2, 2-trimethylpropyl) amino] ethyl] amino] enzonitrile including the pharmaceutically acceptable salts of the same, exhibits an excellent activity promoting hair growth. The above (S) enantiomer of the invention has structure II II The (S) II enantiomer will be in a substantially pure form, that is, the (S) enantiomer will be at least 99% pure and will contain at most 1% of the (R) enantiomer. The enantiomers of the invention form salts with a variety of inorganic and organic acids. Pharmaceutically acceptable, non-toxic salts are preferred, although other salts may also be useful in the isolation or purification of the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, meso-phonic acid, sulfuric acid, acetic acid, maleic acid, and the like. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt is precipitated. The present invention also includes pharmaceutical compositions containing the (R) -enantiomer of 4 - [[(cyanoimino) - [(1,2,2-trimethylpropyl) amino] methyl] amino] benzonitrile or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. In addition, the present invention also includes pharmaceutical compositions containing the (S) -enantiomer of 4- [[(cyanoimino) - [(1,2-trimethylpropyl) amino] methyl] amino] benzonitrile or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. The (R) enantiomer of the invention, ie the (R) -4- [[(cyanoimino) - [(1,2,2-trimethylpropyl) amino] ethyl] amino] benzonitrile, can be prepared in accordance with The following sequence of reactions: (ff) Debhenylation Coupling Reaction Enantiomer (R) i The (S) enantiomer of the invention, ie the (S) -4 - [[(cyanoimino) - [(1,2, 2-trimethylpropyl) amino] methyl] amino] benzonitrile, can be prepared in accordance with sequence of reactions above for the preparation of the (R) -enantiomer, except that the (S) -a -methylbenzyl amine is used instead of the (R) -a-methylbenzylamine, to eventually form NH 2 which is reacted with 4-cyano-N '- (4-cyano phenyl) thiourea, monosodium salt, to form the (S) (II) enantiomer. The (R) I enantiomer of the invention, or the (S) II enantiomer of the invention, can be formulated with other hair growth promoting compounds, such as potassium channel openers, minoxidil (Upjohn) and / or diazoxide (Shiseido and Schering-Plow), as well as chroma, alim and pinacidil; an inhibitor of 5-a-r educt as such as the finasteride (Poroscar ™ from Merck), terazosin hydrochloride (Hytrin ™ from Abbott), or doxaosine mesylate (Cardura ™ from Pfizer); and / or an androgen blocker-such as 4- (5-methoxyheptyl) -hexahydro-2 (1H) -pentalenone as described in PCT Application WO 92/09259A, vasoconstrictors such as dipropionate betamethasone. Asona, the corticosteroids such as hidrocor tis ona, and is copol amine, and cyproterone acetate. The enantiomers of the invention can be administered via the topical, oral, parenteral or rectal routes described in US Patent No. 5,011,837 (incorporated herein by reference), topical administration being preferred. In this manner, the enantiomers of the invention in suitable topical formulations are applied to the region of the skin where hair growth is desired. Topical, typical formulations for use herein, will include ointments, creams, lotions, waxes, gels, pastes, jellies, sprays, aerosols, conventional, and the like, in aqueous or non-aqueous formulations. Examples of suitable topical formulations are described in U.S. Patent Nos. 4,139,619 and 4,596) 812 which are incorporated herein by reference. The enantiomers of the invention will be used in an effective amount, i.e., in an amount sufficient to promote hair growth or treat hair growth disorders., in such a way that it increases or produces hair growth. A typical topical composition will include from about 0.01 to about 15% by weight, preferably from about 0.1 to about 10% by weight of the composition. Topical formulations containing the enantiomers of the invention can be applied to the area to be treated, such as the scalp in humans, by spraying, tapping or rubbing, to deliver the enantiomer to the hair follicle region . The formulations will be applied to the treatment area on a routine basis before, during, or subsequent to hair growth, at least once daily, and preferably two or more times a day. The attached figure is a graph that shows the effect of a once-a-day application of each of the (R) enantiomers and (S) described herein, in hair growth in male C3H mice. The following examples represent preferred embodiments of the present invention.

Example 1 (R) -4- [[(Cyanoimino) - [(1,2-trimethylpropyl) ami] methyl] amino] benzonitrile A. (R) -1, 2, 2-Trimethylpropi lami a The title compound is prepared according to the procedure described by Manley and Quast (J. Med. Ch., 1992, 35, 2327-2340) with some modification. A mixture of pinacolone (29 g, 290 mmol), (R) -a-methylbenzyl (17.6 145 mmol) p-to luensulonic acid monohydrate (300 mg) in toluene (150 L) is refluxed using a trap of Dean-Stark (to remove water from the reaction mixture) for 3 days. The solvent is evaporated and the residue is distilled at approximately 120-122 ° C (9 mm) to give 21 g (71% yield) of as a colorless oil. This material is dissolved in anhydrous THF (210 mL) and treated at a temperature of 0 to 2 ° C with borane-THF complex (1M, 206 mL, 206 mmol). The mixture is wed to reach room temperature, stirred for 5 hours and concentrated in vacuo. To the resulting oily residue, ethanol (300 mL) is carefully added and the mixture is refluxed for 1 hour and again concentrated in vacuo. The residue is chromatographed on basic alumina (grade 1 activity / hexane) to give a colorless oil. Proton NMR and HPLC (YMC C18 S3 4.6 x 50 mm / water-MeOH-H3P04 column, gradient from 90: 10: 0.2 to 10: 90: 0.2) indicates that this material was contaminated with approximately 10% of the tereomer days (MR) . Therefore, this mixture is re-subjected to flash chromatography (silica gel / hexane-EtoAc triethyl amine, 95: 5: 0.1) to produce (11.45 g, 55.8 mmol, yield 54%). The above compound (11.45 g) and 10% pdium on carbon (1.5 g) are taken in EthoH (230 mL) and stirred under hydrogen for 12 hours. The mixture is filtered and the filtrate (approximately 230 mL) containing the title product is used as such for the next step as an approximately 0.24 M solution in ethanol (assumed 100% yield).

B. Monosodium salt of N-Cyano-N '- (4-cyano phenyl) thiourea The title compound is prepared according to Example 1, Part A, of US Patent No. 5,011,837.

C. (R) -4- [[(cyanoimino) - [(1,2,2-trimethylpro-pyl) amino] methyl] amino] benzonitrile To a solution of the compound of Part B (6.0 g, 26.8 mmol) in DMF (150 L), the solution of the compound of Part A (approximately 0.24 M in EthoH, 112 mL, 26.8 mmol) and hydrochloride 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (WSC) (6.0 g, 31.3 mmol). The mixture is stirred at room temperature for 3 hours, diluted with ethyl acetate and washed sequenti with IN HCl, water and brine. The organic layer is dried over magnesium sulfate, concentrated and the crude product is purified by flash chromatography on silica gel (hexanes-ethyl acetate-triethylamine, 75: 25: 0.2) to produce a colorless foam. This material is recrystzed from isopropanol to give the title compound as a white solid (4.15 g, 57.6%), m.p. 159-160 ° C; [α] D-180 ° C C = 1, MeOH; enantomeric purity determined by chiral HPLC = 99% (ChiralPak AD / hexane-isopropane 1-triethi lamina, 80: 20: 0.2 column); MS: 270 (M + H) +; NMR aH (CDC13) d 8.65 (broad s, 1H), 7.69 (d, 2H, J = 8.79 Hz), 7.37 (d, 2H, J = 8.79 Hz), 4.93 (broad d, 1H), 3.83 ( m, 1H), 1.10 (d, 1H), J = 6.45 Hz), 0.90 (s, 9H).

Elemental analysis: calculated for C15H19N5: C, 66.89; H, 7.11; N, 26.00 Found: C, 66.71; H, 7.14; N, 25.98 2 (S) -4- [[(Cyano? Imino) - [(1,2, 2-trimethylpropyl) to i-no] met i 1] amino] ben zoni tri 1 or • The compound of the title is prepared from the compound of Part B of Example 1 and (S) -1,2, 2-trimethylpropyl amine (prepared in accordance with Mandley and Quast, J. Me.D. Ch., 1992, 35, 2327-2340) through the same procedure described in Example 1, Part C.

The product is obtained as a colorless solid, m.p .: 158-159 ° C; [α] D + 189 ° C C = 1, MeOH; enantiomeric purity determined by chiral HP1C = 99.4% (ChiralPak AD / hexane-isopropane 1-triethylamine column, 80: 20: 0.2); MS: 270 (M + H) +; 1H NMR (CDC13) d 8.43 (broad s, 1H), 7.69 (d, 2H, J = 8.79 Hz), 7.37 (D, 2H, J = 8.79 Hz), 4.93 (broad d, 1H), 1.10 ( d, 1H, J = 6.45 Hz), 0.90 (s, 9H).

Example 3 Comparison of the (R) enantiomer of Example 1 and the (S) enantiomer of Example 2, with respect to hair growth in an animal model The objective of the following described experiment was to compare and evaluate the in vivo effect of the (R) enantiomer of Example 1 and the (S) enantiomer of Example 2 on hair growth in an animal model. The two enantiomers were compared topically with respect to hair growth in C3H mice.

Animal Model The C3H model is a useful model for studying hair growth. Its usefulness lies in the fact that the skin pigmentation of this animal is provided with melanocytes from the hair follicle and not from the epidermis. In the telogen or the resting phase of the hair follicle, the skin is pink. In the earlier phase of anagen or the growth phase, the skin suddenly becomes gray and as the anagen phase progresses, the skin becomes darker in color. In this study, visual observation was used as an in vivo assay of the induction of anagen. In addition, as the anagen develops, the thickness of the skin increases from a skin with thin telogen to a skin with thickened, measurable anagen. In this way, the registration of the skin color and the microscopic thickness of the skin of these mice offers a sensible, quantifiable and convenient method to evaluate the phases of hair growth. Groups of 20 male C3H mice, 6 to 7 weeks of age, with hair follicles in the resting phase of hair growth were used. At this stage of your life, the hair follicles remain in the telogen phase for a time 'of up to 30 days or more. This provides a suitable window of time to selectively classify the drugs. The hair growth enhancing compounds simulate hair follicles from telogen to the anagen phase. This stimulation is manifested by the shortening of the telogen phase of the hair follicle cycle. The animals were anesthetized with Cetamine / rompun (100 mg / Kg and 12 mg / Kg) IP and the hair, through a defined dorsal area, was cut flush. Animals with pink skin were treated topically once a day, 5 days a week, with 50 microliters of a 2% solution of the (R) enantiomer of Example 1 and a 2% solution of the (S) enantiomer of Example 1, or vehicle by itself, applied to the dorsal area. The vehicle used was ethanol / propylene glycol / water, 60/30/10. The treatment was continued for at least a time of 4 to 5 weeks. Animals were observed daily for side effects and changes in the test sites. All observations were documented. The test sites were classified weekly regarding changes in skin color and hair growth. In this study the effects of the drug were evaluated using visual observation of skin change from pink to gray and resulting in hair growth.

Resulted The percentage of animals that induced stimulation of the hair follicle during the treatment period is illustrated in the following attached figure. The most significant observation made between the two enantiomers is the difference in the start time of the stimulation of the follicle. The start time for the enantiomer (R) of Example 1 was on day 7 compared to day 11 for the (S) enantiomer of Example 2. The start time for the control vehicle was day 28. For day 11 of the treatment the (R) enantiomer of Example 1 caused stimulation of the hair follicle in 40% of the test mice compared to only 5% with the (S) enantiomer of Example 2. For day 14, 50% of the animals treated with the (R) enantiomer of Example 1 showed a stimulation of the hair follicle, compared with 25% for the (S) enantiomer of Example 2. By day 28, 85% of the animals treated with the (R) enantiomer of Example 1 showed stimulation of the hair follicle compared to 65% treated with the (S) enantiomer of Example 2. In this way, during the treatment period, the group treated with the enantiomer ( R) of Example 1, showed a higher incidence of hair follicle stimulation when compared to the group treated with the (S) enantiomer of Example 2. The attached Figure shows the effect of topical application once a day of the enantiomer (R ) of Example 1 and the (S) enantiomer of Example 2. In conclusion, these results in C3H mice indicate that there is a notable difference between the (R) enantiomer of Example 1 and the (S) enantiomer of Example 2, in its effect on stimulation n hair follicle; in particular the (R) enantiomer has a faster onset of action, compared to the corresponding (S) enantiomer. These results are indeed surprising and unexpected, especially in view of the vasorelax potencies before each of these enantiomers, which is generally recognized as an indication of hair growth promoting properties (Side Effects of Hypertension, 1988, Col. 11, 11-34 to 11-36, and Minoxidil Stimulates Cutaneous Blood Flow in Human Balding Scalps: Pharmacodynamics measured by laser Doppler velocity and photopulse pl and thysmography RC Wester et al, J. Invest. Dermatol., 184, Vol. 82, 515-517). Thus, although the ICS0 for the vasorelax potency of the (R) -enantiomer is 47 ± 17 nM versus 157 ± 35 nM for the (S) enantiomer, as noted above, the hair growth-promoting capacity of the enantiomer ( R), to produce hair growth in 11 days of treatment, is 8 times greater than that of the corresponding (S) enantiomer It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (22)

1. The (R) -enantiomer of 4- [[(cyanoimino) [(1,2, 2-trimethylpropyl) ami-no] me tl] amino] -benzonyl tyl or a pharmaceutically acceptable salt thereof.

2. The (R) -enantiomer according to the definition of claim 1, characterized in that it is substantially separated from its corresponding S-enantiomer.

3. The enantiomer (R) according to the definition of claim 1, characterized in that it has the structure in a substantially pure form

4. The enantiomer (R) according to the definition of claim 1, characterized in that it has an enantiomeric purity equal to at least 99.

5. A pharmaceutical composition characterized in that it comprises the (R) enantiomer according to the definition of claim 1 and a pharmaceutically acceptable carrier therefor.

6. A pharmaceutical combination characterized in that it comprises the R-enantiomer according to the definition of claim 1, in combination with another hair growth promoting agent.

7. A method for promoting hair growth, characterized in that it comprises administering to a human in need of treatment, a therapeutically effective amount of the (R) -enantiomer of 4- [[(cyanoimino) [(1,2-trimethylpropyl) amino]] et il] aminojbenzoni t or a pharmaceutically acceptable salt thereof.

The method according to the definition rei indication 7, characterized in that the (R) enantiomer is administered either therapeutically or topically.

9. The method according to the definition of claim 7, characterized in that the (R) enantiomer is administered topically.

10. The method according to the definition of claim 7, characterized in that the (R) -enantiomer is administered as a cream formulation, a lotion formulation, a liquid formulation or an ointment formulation.

11. A method for the treatment of male pattern baldness, characterized in that it comprises administering to a human in need of treatment, a therapeutically effective amount of the (R) -enantiomer as defined in claim 1.

12. The (S) -enantiomer of 4- [[(cyanoimino) [(1,2,2-trimethylpropyl) amino] -methyl] amino] -benzonyl t-yl or a pharmaceutically acceptable salt thereof.

13. The (S) -enantiomer according to the definition of claim 12, characterized in that it is substantially separated from its corresponding (R) -enantiomer.

14. The enantiomer (S) according to the definition of claim 12, characterized in that it has the structure in a substantially pure form

15. The enantiomer (S) according to the definition of claim 12, characterized in that it has a purity enanti or ér i ca equal to at least 99%.

16. A pharmaceutical composition characterized in that it comprises the (S) enantiomer according to the definition of claim 12 and a pharmaceutically acceptable carrier therefor.

17. A pharmaceutical combination characterized in that it comprises the (S) enantiomer according to the definition of claim 12, in combination with another hair growth promoting agent.

18. A method for promoting hair growth, characterized in that it comprises administering to a human in need of treatment, a therapeutically effective amount of the (S) -enantiomer of 4- [[(cyanoimino) [(1,2-trimethylpropyl) amino]] methyl] amino] benzonyl t or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18, characterized in that the (S) enantiomer is administered systemically or topically.

20. The method according to the definition of claim 18, characterized in that the (S) enantiomer is administered topically.

21. The method according to the definition of claim 18, characterized in that the (S) -enantiomer is administered as a cream formulation, a lotion formulation, a liquid formulation or an ointment formulation.

22. A method for the treatment of male pattern baldness, characterized in that it comprises administering to a human in need of treatment, a therapeutically effective amount of the (S) -enantiomer as defined in rei indication 12.