METHODS, COMPOSITIONS AND SOLUTIONS FOR TREATING ALOPECIA

Abstract: Method for treating the form of alopecia commonly known as ''male pattern baldness'' which comprises regular topical application to the affected areas of the human scalp of a composition containing as at least one of its active ingredients of Formula I, wherein: either one of R1 and R2 is hydrogen and the other is selected from the class of C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C1-6 alkylsuphinyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylthiocarbonyl, C1-6 alkoxythiocarbonyl, C1-6 alkylthiocarbonyloxy, C1-6 alkoxythiolmethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulphinylamino, C1-6 alkylsulphonylamino, C1-6 alkoxysulphinylamino or C1-6 alkoxysulphonylamino or ethylenyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2, or one or R1 and R2 is nitro, cyano or C1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C1-6 alkyl or by C2-7 alkanoyl; one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl or R3 and R4 together are C2-5 polymethylene; either R5 is hydrogen, hydroxy, C1-6 alkoxy or C1-7 acyloxy and R6 is hydrogen or R5 and R6 together are a bond; R7 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl or carboxy, C1-6 alkyl substituted by halogen, or C2-6 alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of C1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C1-12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C1-6 alkyl groups; R8 is hydrogen or C1-6 alkyl; or R7 and R8 are joined together to form C3-5 polymethylene or -CH2-(CH2)n-Z-(CH2)m- where m and n are integers 0 to 2 such that m+n is 1 or 2 and Z is oxygen, sulphur or NR9 wherein R9 is hydrogen, C1-9 alkyl, C2-7 alkanoyl, phenyl C1-4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C1-6 alkyl, C1-6 alkoxy or halogen; mono- or bi-cyclic heteroarylcarbonyl; X is oxygen or sulphur; and the R8NCXR7 moiety is trans to the R5 group when R5 is hydroxy, C1-6 alkoxy or C1-7 acyloxy; or a pharmaceutically acceptable salt or solvate thereof.

Description: METHODS , COMPOSITIONS AND SOLUTIONS FOR TREATING ALOPECIA BackEround and Summary The present invention relates to methods, compositions solutions for treating human alopecia, including male pattern alope (androgenic alopecia) and alopecia areata, involving the use of substance known as BRL-34915 and related 4-amino and 4-ami substituted chromans, chromenes, and chromanols of Formula I, association with a pharmaceutical carrier adapted for topi application. European Patent Publication Nos. 76075, 91748, 93535, 953 107423, 120426, 120427, 126311, 126350, 126367, 138134 and 173 describe- classes of chromanols, chromenes and chromans hav an ihyper ensive activity and that they are of potential use in treatment of other cardiovascular disorders. Such disorders incl congestive heart failure, angina, peripheral vascular disease cerebral vascular disease. Dermatologists recognize many different types of hair loss, t most common by far being "androgenic alopecia" wherein human mal begin losing scalp hair at the temples and on the crown of the head they get older. While this type of hair loss is largely confined males, hence its common name "male pattern baldness", it is not unkno in women. Dr. Charles A. Chidsey, III and Dr. Guinter Kahn disclose a claim in U.S. Patent 4,596,812 the use of minoxidil, 6-amino-l, dihydro-l-hydroxy-2-imino-4-piperidinopyrimidine, as a therapeut agent to treat alopecia and arrest and reverse male pattern alopeci See also U.S. Patent 4,139,619 which claims the use of minoxidil a related 6-amino-4-(substituted amino)-1,2-dihydro-l-hydroxy- iminopyrimidines as a means for (a) increasing the rate of growth terminal hair, and (b) converting vellus hair to growth as termin hair. The use of retinoids alone or in combination with minoxidil a related substituted pyrimidines to increase the rate of hair growth disclosed in PCT publication numbers US85/04577, PCT US83/02558 and P US82/02833. The use of minoxidil sulphate (2,6, -diamino-4-(1-piperidinyl)- (sulfooxy)-pyrimidinitim hydroxide, inner salt) as a therapeutic ager. to stimulate the rate of hair growth Is disclosed in PCT Applicatio US86/00073, filed 23 January 1986. In addition, the induced relaxatio of rabbit superior mesenteric artery smooth muscle by minoxidi sulphate and dependence on potassium permeability has been reported See K.D. Melsheri, et al, "The Mechanisms of Vascular Smooth Muscl Relaxing Effects of Minoxidil Sulfate"; Smooth Muscle Functio Symposium Proceedings: Official Satellite Symposium of the XX Internation Congress of the International Union of Physiologica Sciences, Banff Center, Banff, Canada, 1986, page 114, abstract W4-P5. Notwithstanding the fact that nothing before the use of topica application of minoxidil had been found which was effective I preventing, let alone reversing, male pattern baldness, a good deal i known about various types of human hair and its growth patterns o various parts of the body. For purposes of the present invention, we need only consider tw types o.f hair, namely "terminal hairs" and "vellus hairs". Termina hairs are coarse, plgmented, long hairs in which the bulb of the hai follicle is seated deep in the dermis. Vellus hairs, on the othe hand, are fine, thin, non-pigmented short hairs in which the hair bul is located superficially in the dermis. As alopecia progresses, transition takes place In the area of approaching baldness wherein th hairs themselves are changing from the terminal to the vellus type. Another factor that contributes to the end result is a change i the cycle of hair growth. All hair, both human and animal, passe through a life cycle that Includes three phases, namely, (1) the anage phase (2) the catagen phase and (3) the telogen phase. The anage phase Is the period of active hair growth and, insofar as scalp hair i concerned, this generally lasts from 3-5 years. The catagen phase Is short transitional phase between the anagen and telogen phases which in the case of scalp hair, lasts only 1-2 weeks. The final phase i the telogen phase which, for all practical purposes, can be denominate by a "resting phase" where all growth ceases and the hair eventually i shed preparatory to the follicle commencing to grow a new one. Scal hair in the telogen phase is also relatively short-lived, some 3 months elapsing before the hair is shed and a new one beings to grow. Now, under normal hair growth conditions on the scalp approximately 88% of the hairs are in the anagen phase, only 1% catagen and the remainder in telogen. With the onset of male patt baldness, a successively greater proportion of the hairs are in telogen phase with correspondingly fewer in the active growth ana phase. The remaining result associated with alopecia is the seve diminution of hair follicles. A bald human subject will average o about 306 follicles per square centimeter, whereas, a non-bald one the same age group (30-90 years) will still have an average of 4 follicles per square centimeter. This amounts to a one-third reducti in hair follicles which, when added to the increased proportion vellus hair follicles and the increase number of hair follicles telogen, is both significant and noticeable. It is written th approximately 50% of the hairs must be shed to produce visible thinni of scalp hair. It is thus a combination of these factors: ( transition of hairs from terminal to vellus, (2) increased number telogen hairs - some of which have been shed, and (3) loss of ha follicles (atrophy in Settel's description) that produces "baldness". Now, while a good deal is known about the results of male patte baldness, very little is known about its cause. About all that can said is that the cause is felt to be genetic and hormonal in orig although as will be seen presently, the known prior art attempts control it through hormone adjustment have been singular unsuccessful. At the present time, one known treatment for male pattern alopec is hair transplantation. Plugs of skin containing hair a transplanted from areas of the scalp where hair is growing to ba areas with reasonable success; however, the procedure is a costly o in addition to being time-consuming and quite painful. Furthermore the solution is inadequate from the standpoint that it becomes practical, if not an economic, impossibility to replace but a tin fraction of the hair present in a normal healthy head of hair. As far as the other non-drug related approaches to the problem ar concerned, they include such things as ultra-violet radiation, massage psychiatric treatment and exercise therapy. None of these, however has been generally accepted as being effective. Even such things a revascularization surgery and acupuncture have shown little, if any promise . By far, the most common approach to the problem of discovering remedy for male pattern alopecia has been one of drug therapy. Man types of drugs ranging from vitamins to hormones have been tried an only recently has there been any indication whatsoever of even moderat success. For instance, it was felt for a long time that since a androgenic hormone was necessary for the development of male patter baldness, that either systemic or topical application of a antiandrogenic hormone would provide the necessary inhibiting action t keep the baldness from occurring. The theory was promising but th results were uniformly disappointing. The androgenic hormone testosterone was known, for example, t stimulate hair growth when applied topically to the deltoid area a well as when Injected into the beard and pubic regions. Even ora administration was found to result in an increased hair growth In th beard and pubic areas as well as upon the trunk and extremities. Whil topical application to the arm causes increased hair growth, it I ineffective on the scalp and some thinning may even result. Heav doses of testosterone have been even been known to cause male patter alopecia. Certain therapeutic agents have been known to Induce hair growt in extensive areas of the trunk, limbs and even occasionally on th face. Such hair is of intermediate status in that it is coarser tha vellus but not as coarse as terminal hair. The hair is generally quit short with a length of 3 cm being about maximum. Once the patien ceases taking the drug, the hair reverts to whatever is normal for th particular site after six months to a year has elapsed. An example o such a drug is diphenylhydantoin which is an antlconvulsant drug widel used to control epileptic seizures. Hypertrlchosis is frequentl observed in epileptic children some two or three months after startin the drug and first becomes noticeable on the extensor aspects of th limbs and later on the trunk and face. The pattern is not unlike tha sometimes caused by injury to the head. As for the hair, it is ofte shed when the drug is discontinued but may, In some circumstances, remain. "Minoxidil", as was true with "Diazoxide", produced a good deal o hypertrichosis in patients to whom the drug was administered. See, fo example, Journal of Laboratory and Clinical Medicine, Vol. 79, p 639, April, 1972; Circulation, Vol. 45. page 571, March 1972; Clinical Pharmacy and Therapy, Vol. 13. page 436, 1972. Streptomycin is another drug that has been found to produce hyp trichosis in much the same way as diphenylhydantoin when administe to children suffering from tuberculous meningitis. About the s effects were observed and the onset and reversal of the hypertricho in relation to the period of treatment with the antibiotic leave lit question but that it was the causative agent. The compounds of the subject invention (Formula I) includi namely, 6-cyano-3,4-dihydro-2 , 2-dimethyl-trans-4-(2-oxo pyrrolidinyl)-2H-benzo[b]pyran-3-ol and trans-4-N-acetyl-ethylamino cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol, are far differ from diazoxide, and the 6-amino-4-(substituted amino)-1,2-dihydro hydroxy-2-iminopyrimidines of U.S. Patent 4,139,619 and 4,596,812. The compound 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo pyrrolidinyl)-2H-benzo[b]pyran-3-ol, hereinafter to be referred to the coined term "BRL-34915", was disclosed by J.M. Evans, R. Buckingham and . Willcocks and it forms the subject matter among ot similar compounds of U.S. Patent 4,446,113 issued May 1, 1984. Example 1 of U.S. Patent 4,446,113. This compound, among others Formula I, has been reported as a potent vasodilator anti-hypertens agent and is currently under preclinical evaluation. It is a so-cal direct acting "vasodilator" which, as the name implies, functions dilate the peripheral vascular system. It is reported to act in novel manner for an anti-hypertensive agent to cause hyperpolarisati of the cell membrane by activation of the outward conductance potassium ions. The cell membrane is desensitized and the inwa movement of calcium is reduced in a way different from that of t calcium antagonist nifedipine See e.g., Br. J. Pharmac. (1986), 8 121-128 and Br. J. Pharmac. (1986). 88, 103-111. It has not be reported to produce hypertrichosis so far as applicants are aware. Minoxidil is a known vasodilator. Following reports of the use minoxidil and related compounds to stimulate hair growth, and as treatment of male pattern alopecia, other vasodilators includi "viprostol" and "diazoxide" are reported as being evaluated by othe to stimulate hair growth. See for example U.S. Patent Nos. 4,431,8 and 4,311,707; European Patent 027,665 (published 04/29/81). Vasodilators as a general class of therapeutic agents have, so far as applicants are aware, never proven effective to grow hair on th scalp as a result of topical application thereof to bald areas. It is, therefore, the principal object of the present invention to provide a novel, unobvious and effective treatment for male patter baldness. Another object of the invention forming the subject matter hereo is to provide a method of treating certain types of baldness in human that is compatible with various types of therapeutic agents or carriers and, therefore, would appear to be combinable with those which, b themselves, demonstrates some therapeutic activity such as, fo example, mlcroemulsion creams containing estradiol and oxandrolone. Still another objective is the provision of a treatment fo alopecia which, while effective for its intended purpose, is apparentl non-toxic and relatively free of unwanted side effects. An additional object of the invention herein disclosed and claime is to provide a method for treating baldness in men which comprises application of a compound of Formula I by the patient himself under medical supervision no more stringent than that demanded for othe topically-administered therapeutic agents. Other ob ects of the invention are to provide a treatment for male pattern alopecia which is safe, simple, painless, cosmetic in the sense of being Invisible, easy to apply and quite inexpensive when compared with hair transplanted and the like. Further objects will be In part apparent and in part pointed out specifically hereinafter in connection with the detailed description of the invention which follows. Dermatologists and others were well aware of the fact that prolonged vasodilation of certain areas of the human body other than the scalp sometimes resulted in Increased hair growth even in the absence of any vasodilating therapeutic agent. For Instance, increased hair growth around surgical scars is not uncommon. Similarly, arteriovenous fistula have been known to result In Increased vascularity accompanied by enhanced hair growth. Externally-induced vasodilation of the skin, such as, for example, by repeated biting of the limbs by mental retardates and localized stimulation of the shoulders bv water carriers has been noted to bring on hypertricho in the affected areas. Be that as it may, similar techniques such continued periodic massage of the scalp have been found tota ineffective as a means for restoring lost hair growth to the sca Scar tissue on the scalp inhibits rather than promotes hair growth. Detailed Description This invention relates to the method for treating alopec including androgenic alopecia (male pattern baldness; male patt alopecia) and alopecia areata, which comprises regular topic application to the affected areas of the human skin a pharmaceutic composition containing as at least one of its active ingredients compound of Formula I. It also encompasses the use of a compound Formula I as a therapeutic agent to arrest and reverse androgen alopecia. The compounds of this invention are represented by Formula wherein either one of R_ and R2 is hydrogen and the other is selected from t class of Cl-6 alkylcarbonyl, ^1-6 alkoxycarbonyl, c l alkylcarbonyloxy, Cl-6 alk lhydroxymethyl, nitro, cyano, chlor trifluoromethyl, C^.g alkylsulphinyl, C^. alkylsulphonyl, C^ alkoxysulphinyl, C^.g alkoxysulphonyl, C^. alkylcarbonylamino, C^ alkoxycarbonylamino, C ] _.g alkyl-thiocarbonyl, C^.g alkoxythiocarbony C^. alkylthiocarbonyloxy, c l-6 alkoxythiolmethy1, formyl aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety bei optionally substituted by one or two C^.g alkyl groups, or C ] _ alkylsulphinylamino, C^.g alkylsulphonylamino C ] __ alkoxys-tlphinylami or C ] __ alkoxysulphonylamino or ethylenyl terminally substituted by C g alkylcarbonyl, nitro or cyano, or -C(Cι_g alkyl)N0H or - (C^ alkyl) NH2, or one of R^ and R2 is nitro, cyano or C^.3 alkylcarbon and the other is methoxy or amino optionally substituted by one or t C^.g alkyl or by C2-7 alkanoyl; one of R3 and R4 is hydrogen or C__^ alkyl and the other is C_ alkyl or R3 and R together are C2.5 polymethylene; either R5 is hydrogen, hydroxy, C^.g alkoxy or C ] __ 7 acyloxy and is hydrogen or R5 and Rg together are a bond; R7 is hydrogen, C^. alkyl optionally substituted by hydroxy, C^_ alkoxy, C^. alkoxycarbonyl or carboxy, C^.g alkyl substituted b halogen, or C2_ alkenyl: aryl or heteroaryl either being optionall substituted by one or more groups or atoms selected from the class o C^.g alkoxy, hydroxy, halogen, trlfluoromethyl, nitro, cyano. C\. _ carboxylic acyl, or amino or aminocarbonyl optionally substituted b one or two Cι_ alkyl groups; Rg is hydrogen or C^_ alkyl; or R and Rg are joined together to form C .5 polymethylene or -CH2 CH2) n -Z-(CH2)m- where m and n are integers 0 to 2 such that m+n is or 2 and Z Is oxygen, sulphur or NRQ wherein Rg is hydrogen, C _ alkyl, c 2-7 alkanoyl, phenyl G_- alkyl, naphthylcarbonyl phenylcarbonyl or benzylcarbonyl optionally substituted in the pheny or naphthyl ring by one or two Cι_g alkyl, C _g alkoxy or halogen mono- or bi-cyclic heteroarylcarbonyl; X is oxygen or sulphur; and the RgNCXR 7 moiety is trans to the R group when R5 is hydroxy, C^.g alkoxy or C^_ 7 acyloxy: or pharmaceutically acceptable salt or solvate thereof. Examples of 7 aryl include phenyl and naphthyl. Examples of R 7 heteroaryl include 5- or 6-membered monocyclic o 9- or 10-membered bicyclic heteroaryl. In addition, 5- or 6-membere monocyclic or 9- or lO-membered bicyclic heteroaryl can be optionall contain one, two or three heteroatom which are selected from the clas of oxygen, nitrogen and sulphur and which, In the case of there bein more than one heteroatom, are the same or different. Suitable values for R , when R 7 and Rg are not joined togethe include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert butyl. Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furanyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadlazolyl, and pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Preferred examples of suc groups include furanyl, thienyl, pyrryl and pyrldyl, in particular 2- and 3-furanyl, 2- and 4-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4 pyridlnyl. Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl. benzothiophenyl, indolyl an indazolyl, quinolinyl and isoquinolinyl, and quinazoninyl. Examples of the groups or atoms for optional substitution or a or heteroaryl include methyl, methoxy, hydroxy, chloro, nitro or cya Examples of a pharmaceutically acceptable salt of a compound formula (I) include the acid addition salts of a compound of form (I) , wherein one or other of R^ and R2 is amino or an amino-contain group, for example the hydrochloride and hydrobromide salts. Examples of a pharmaceutically acceptable solvate of a compound formula (I) include the hydrate. The compounds of formula (I), wherein R5 is hydrogen, hydroxy, g alkoxy or \.η acyloxy and Rg is hydrogen, are asymmetric a therefore, can exist in the form of optical isomers. The pres invention extends to all such isomers individually and as mixtur including racemic modifications. The compounds of Formula I and methods for their preparation disclosed in U.S.Patent Nos. 4,446,113, 4,481,214, 4,496,565 4,510,152 and allowed U.S. Serial Nos. 482,628 and 592,117. ( subject matter of which are all expressly incorporated herein reference), or by analogous methods thereto. See also J. Med. Ch 27, 1127-1131 (1984), J. Med. Chem. 26, 1582-1589 (1983) and Europ Patent Application No. " 173,848, published 03/12/86. Examples of the compounds of Formula I include the exampl described in the aforementioned U.S. patents as well as aforementioned European patent applications. A class of compounds within Formula I are those of Formula I wherein P is 1 or 2 and the remaining variables are as defined Formula I. The compounds of Formula II can be used in the same mann as the compounds of Formula I. The pharmaceutical compositions contemplated by this inventi include pharmaceutical compositions adapted for topical application the human scalp. Conventional pharmaceutical forms for this purpo include ointments, lotions, pastes, jellies, gels, mousses, spray foams, aerosols, and the like. The term "ointment" embrac formulations (including creams) having oleaginous, absorption, wate soluble and emulsion-type bases, e.g., petrolatum, lanoli polyethylene glycols, as well as mixtures of these. The compounds m also be formulated into conventional lipsomal preparations or dissolv in conventional solvents such as acetonitrile , dimethylformamide (DMF) , dimethylacetamide (DMA) , alcohol , propanol , and the like . The percentage by weight of the compound of the formula I herei utilized ranges from about 0.005% to about 10.0% of the pharmaceutica preparation, preferably from about 0.05% to about 3 .0% and in thes preparations the aforesaid pharmaceutical carrier for topica application constitutes a maj or amount of the said preparation. The pharmaceutical preparations of the subj ect invention ar applied on a regular basis , with or without occlusion, for a period o time sufficient to effect hair growth. Occlusion of the preparatio may be obtained by any conventional means such as bandages , plasti coverings , shower caps swimming caps , etc . The percentage of activ ingredient (Formula I) as well as frequency of application may b varied as necessary or desirable to achieve the desired results . Example 1 Two hundred and fifty liters of a pharmaceutically elegant 2% topical solution of BRL- 34915 is prepared from: Propylene Glycol USP 51 kg 800 g (Sp .Gr . - 1.036) BRL- 34915 (Milled) (5 kg) 5 kg 030 g Alcohol USP q. s . ad 250 L The propylene glycol and 150 L. of alcohol are added to a mixing tank, the BRL- 34915 is added and dissolved in the propylene glycol/alcohol mixture and additional alcohol added to make 250 liters . The resulting BRL- 34915 topical solution is packaged in suitable dispensing bottles , accompanied by a etered dropper, and applied to the pre-washed scalp as a total dose of 1 ml , beginning in the center of the affected area. Twice daily application for 2 to 7 months or longer may be require before evidence of hair growth stimulation can be expected in the treatment of early r progressive male pattern baldness . Onset and degree of hair growth stimulation can be expected to vary considerably among patients . 0.1% and 1% BRL- 34915 topical solutions are prepared in accordance with the foregoing procedure by utilizing 0.25 kg and 2.5 kg, respectively of BRL- 34915 for the 5.0 kg utilized in the preparation of the 2% solution of Example 1. Example 2 Pharmaceutically el-egant 0.5, 1.5 and 3% BRL-34915 gels prepared by mixing the below-described 3 part mixtures: A. Topical BRL-34915 gel 0.5% Part I % w/w Purified water USP q-s. 100 Carbopol 934P 0. 45 Part II BRL-34915 0. 5 Propylene glycol USP 1C ) Alcohol USP 13 Diisopropanolamine NF 0. 45 Part III Alcohol USP 27 B. Topical BRL-34915 gel 1.5% Part I % w/w Purified water USP q.s. 100 Carbopol 934P 0.5 Part II Propylene glycol USP 20 Alcohol USP 13 BRL-34915 1.5 Diisopropanolamine NF 0.5 Part III Alcohol USP 27 C. Topical BRL-34915 gel 3% Part I % w/w Purfied water USP q.s. 100 Carbopol 934P 0.5 Part II BRL-34915 3.0 Propylene glycol USP 30 Alcohol USP 13 Diisopropanolamine NF 0.5 Part III Alcohol USP 27 In each of the above cases, the component parts are prepare separately. Parts I and III are each mixed in a Nauta Mixer unde vacuum. Part III is then mixed with Part I. When a uniform mixture i obtained, Part II is then added using planetary mixing under vacu until a uniform gel is obtained. Following the procedure of the preceding Examples 1 and 2 inclusive, compositions are similarly prepared substituting a equimolar amount of another compound within the scope of Formula I fo BRL-34915. Following the procedure of the preceding Examples 1 and 2 inclusive, compositions are similarly prepared substituting a equimolar amount of trans-4-N-acetyl-ethylamino-6-cyano-3,4-dihydro 2,2-dImethyl-2R-ber_zo[b]pyran-3-ol (the compound of example 1 of U.S Patent 4,481,214) for BRL-34915. Thus, it is intended that modifications and variations of t present invention, which have been hereinbefore disclosed or suggeste be included within the scope of the appended claims except insofar a limited by the prior art. F0R.MU A (ID

Claims: CLAIMS 1. A method of treating humans for alopecia which comprises topically applying to the human scalp an effective amount of a pharmaceutical composition containing a compound of Formula I wherein; either one of Ri and R2 is hydrogen and the other is selected from the class of Cχ_g alkylcarbonyl, c l-6 alkoxycarbonyl, Cχ. alkylcarbonyloxy, c l-6 alkylhydroxymethy1, nitro, cyano, chloro. trifluoromethyl, c l-6 alkylsulphinyl, c _-6 alkylsulphonyl, C .g alkoxysulphinyl, Cχ_g alkoxysulphonyl, Cχ.g alkylcarbonylamino, Cχ_g alkoxycarbonylamino, Cχ_g alkyl-thiocarbonyl, Cχ.g alkoxythiocarbonyl, Cχ_g alkylthiocarbonyloxy, C .g alkoxythiolmethy1, formyi or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two Cχ_g alkyl groups, or C _g alkylsulphinylamino, C _g alkylsulphonylamino C _g alkoxysulphlnylamino or Cχ_g alkoxysulphonylamino or ethylenyl terminally substituted by C^_ g alkylcarbonyl, nitro or cyano, or -C(Cχ.g alkyl)N0H or -C(C .g alkyl)N H2, or one of ^ and R2 is nitro, cyano or C .3 alkylcarbonyl and the other Is methoxy or amino optionally substituted by one or two C .g alkyl or by C2-7 alkanoyl; one of R3 and R4 is hydrogen or C _ alkyl and the other is C__^ alkyl or R3 and R together are -2-5 polymethylene; either R5 is hydrogen, hydroxy, C .g alkoxy or C-__ j acyloxy and Rg is hydrogen or R5 and Rg together are a bond; R7 is hydrogen, Cχ.g alkyl optionally substituted by hydroxy, Ci _ alkoxy, Cχ_g alkoxycarbonyl or carboxy, Cχ. alkyl substituted by halogen, or C2_g alkenyl; aryl or heteroaryl either being optionallv substituted by one or more groups or atoms selected from the class of C .g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C .g alkyl groups; Rg is hydrogen or C^.g alkyl: or R 7 and Rg are joined together to form C .5 polymethylene or - (CH2) n -Z- (CH2)m- where m and n are integers 0 to 2 such that m+n i or 2 and Z is oxygen, sulphur or NRg wherein Rg is hydrogen, C alkyl, ^2-7 alkanoyl, phenyl c i- alkyl, naphthylcarbon phenylcarbonyl or benzylcarbonyl optionally substituted in the phe or naphthyl ring by one or two ^. alkyl, Cχ_g alkoxy or halog mono- or bi-cyclic heteroarylcarbonyl; X is oxygen or sulphur; and the R CXR7 moiety is trans to the group when R5 is hydroxy, C _ alkoxy or C^.7 acyloxy; or pharmaceutically acceptable salt or solvate thereof. 2. The method as defined in claim 1 wherein the compound of Formul is 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4- (2-oxo-1-pyrrolidinyl)- benzo[b]pyran-3-ol. 3. The method as defined in Claim 1 wherein the compound of Formul is trans-4-N-acetyl-ethylamino-6-cyano-3,4-dihydro-2,2-dimethyl- benzo[b]pyran-3-ol. 4. The method as defined In claim 1 wherein the compound of Formul is present in the composition in an amount of from about 0.005% about 10%. 5. The method as defined in Claim 2 wherein the compound is pres in the composition in an amount of from about 0.05% to about 3.0%. 6. The method as defined in Claim 3 wherein the compound is pres in the composition in an amount of from about 0.05% to about 3.0%. 7. The method of arresting and reversing male pattern alopecia whi comprises continued periodical topical application to the human sc of a physiologically effective dose of a compound of Formula I wherein; either one of Ri and R2 is hydrogen and the other is selected fro the class of C .g alkylcarbonyl, C .g alkoxycarbonyl, Cχ_ alk lcarbonyloxy, Cχ_g alkylhydroxymethyl, nitro, cyano, chloro trifluoromethyl, Cχ_g alkylsulphinyl, Cχ.g alk lsulphonyl, Cχ. alkoxysulphlnyl, C _g alkoxysulphonyl, C .g aIkylcarbonylamino, C^. alkoxycarbonylamino, C _g alkyl-thiocarbonyl, C^.g alkoxythiocarbonyl Cχ_g alkylthiocarbonyloxy, c l-6 alkoxythiolmethy1, formyl o aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety bein optionally substituted by one or two Cχ_g alkyl groups, or C _ alkylsulphinylamino, Cχ_g alkylsulphonylamino C .g alkoxysulphlnylamin or Cχ.g alkoxysulphonylamino or ethylenyl terminally substituted by C g alkylcarbonyl, nitro or cyano, or -C(Cχ_g alkyl)N0H or -C(Cχ_ alkyl)NNH2, or one of R_ and R2 is nitro, cyano or Cχ_3 alkylcarbony and the other is methoxy or amino optionally substituted by one or tw C .g alkyl or by C2-7 alkanoyl; one of R3 and R Is hydrogen or C _ alkyl and the other is C . alkyl or R3 and R together are C2_5 polymethylene; either R5 is hydrogen, hydroxy, Cχ.g alkoxy or Cχ_ acyloxy and R is hydrogen or R_ and Rg together are a bond; R7 is hydrogen, Cχ_g alkyl optionally substituted by hydroxy, Cχ_ alkoxy, Cχ_g alkoxycarbonyl or carboxy, C .g alkyl substituted b halogen, or C2_ alkenyl; aryl or heteroaryl either being optionall substituted by one or more groups or atoms selected from the class o C _g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, carboxylic acyl, or amino or aminocarbonyl optionally substituted b one or two Cχ.g -alkyl groups; Rg is hydrogen or Cχ.g alkyl; or R7 and Rg are joined together to form 03.5 polymethylene or -CH2 / (CH2) n -Z- (CH2) - where m and n are integers 0 to 2 such that m+n i or 2 and Z is oxygen, sulphur or NRg wherein Rg is hydrogen, C alkyl, C2-7 alkanoyl, phenyl ^1-4 alkyl, naphthylcarbon phenylcarbonyl or benzylcarbonyl optionally substituted in the phe or naphthyl ring by one or two C^.g alkyl, Cχ_g alkoxy or halog mono- or bi-cyclic heteroarylcarbonyl; X is oxygen or sulphur; and the RgNCXR7 moiety is trans to the group when R_ is hydroxy, Cχ.g alkoxy or C .7 acyloxy; or pharmaceutically acceptable salt or solvate thereof; in association with a topical pharmaceutical carrier. 8. The method as defined in claim 7 wherein the compound of Formul is 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrro1idiny1)- benzo[b]pyran-3-ol. 9. The method as defined in Claim 7 wherein the compound of Formul is trans-4-N-acetyl-ethylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2 benzo[b]pyran-3-ol. 10. The method as defined in Claim 8 wherein the compound of Formula is present in the composition in an amount of from about 0.005% about 10%. 11. The method as defined in Claim 9 wherein the compound of Formula is present in the composition in an amount of from about 0.005% about 10%. 12. A topical pharmaceutical solution for the treatment of alopec consisting of a compound of Formula I wherein; either one of R^ and R2 Is hydrogen and the other is selected from the class of C _g alkylcarbonyl, ^1-6 alkoxycarbonyl, Cχ.g alk lcarbonyloxy, c i-6 alk lhydroxymethyl, nitro, cyano, chloro, t ifluoromethyl, c χ_6 alkylsulphinyl, C±-ζ alkylsulphonyl, c i-6 alkoxysulphinyl, Cχ_g alkoxysulphony1, C .g alkylcarbonylamino, .C _g alkoxycarbonylamino, Cχ.g alkyl-thiocarbonyl, Cχ.g alkoxythiocarbonyl, Cχ_g alkylthiocarbonyloxy, Cχ-6 alkoxythiol ethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C . alkyl groups, or C _g alkylsulphinylamino, Cχ.g alkylsulphonylamino Cχ.g alkoxysulphlnylamino or Cχ.g alkoxysulphonylamino or ethylenyl terminally substituted by C _ g alkylcarbonyl, nitro or cyano, or -C(Cχ.g alkyl)N0H or -C(Cχ_g alkyl)NNH2, or one of ^ and R2 is nitro, cyano or Cχ_3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two Cχ_g a Ik l or by C2-7 alkanoyl; one of R3 and R4 is hydrogen or C _4 alkyl and the other is C .4 alkyl or R3 and R4 together are C2.5 polymethylene; either R5 is hydrogen, hydroxy, Cχ_g alkoxy or Cχ_7 acyloxy and Rg is hydrogen or R5 and Rg together are a bond; R7 Is hydrogen, Cχ_g alkyl optionally substituted by hydroxy, C _g alkoxy, Cχ_g alkoxycarbonyl or carboxy, Cχ.g alkyl substituted by halogen, or C2_ alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of C .g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C . 2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cχ_g alkyl groups; Rg is hydrogen or Cχ.g alkyl; or R 7 and Rg are joined together to form C3.5 polymethylene or -C (C_-2) n -Z- (CH2)m- where and n are integers 0 to 2 such that m+n i or 2 and Z is oxygen, sulphur or NRg wherein Rg is hydrogen, C alkyl, ^2-7 alkanoyl, phenyl c i-4 alkyl, naphthylcarbon phenylcarbonyl or benzylcarbonyl optionally substituted in the phe or naphthyl ring by one or two Cχ_ alkyl, C^.g alkoxy or halog mono- or bi-cyclic heteroarylcarbonyl; X is oxygen or sulphur; and the R CXR moiety is trans to the group when R5 is hydroxy, Cχ.g alkoxy or Cχ. 7 acyloxy; or pharmaceutically acceptable salt or solvate thereof; in association with a vehicle which adapts said solution topical application to the human skin.

Inventors: HESTER JACKSON B JR, MEISHERI KAUSHIK D, HESTER, JACKSON, B., JR., MEISHERI, KAUSHIK, D.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1987
Main classification: A61K7
IPC codes: A61K8, A61K31, A61P17, A61Q5, A61Q7, C07D311, C07D405