CN1320028A - Method of treating hair loss using sulfonamides - Google Patents

Abstract

The present disclosure describes methods for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The methods comprise administering a compound having a structure as described herein and a pharmaceutically-acceptable carrier.

Description

Use the method for sulfonamide treatment alopecia

Invention field

The present invention relates to treat the method for mammal alopecia, the alopecia of described treatment mammal comprises prevention and/or reverse hair loss and promotes hair growth.

Cross-index

According to the 35th of United States code the 119th (e), the application is a priority with the provisional application serial number 60/102,448 of JIUYUE in 1998 submission on the 30th.

Background technology

Alopecia is a kind of FAQs, this be produce owing to for example natural process or be that the medicine that designs as cancer that palliates a disease impels generation by chemical method usually because of using some.This class alopecia is attended by the long shortage of hair regeneration usually, thereby causes the bald or alopecia totalis of part.This class alopecia considers to lack captivation from angle attractive in appearance, and the people of experience alopecia is worried especially.

Just as known in the art, hair growth is by causing the activity cycle that comprises the alternate periods of growing and having a rest.This cycle is divided into the anagen of being known as usually, three Main Stage of catagen and telogen.The anagen be the trophophase in described cycle, it can be characterized as being hair follicle and penetrate deep dermis, the cell fast breeding that is breaking up simultaneously and form hair.Next stage is catagen, and this stage is a transition stage, and its sign is fissional stopping, and passes corium at this stage hair follicle and degenerates and hair growth stops.Next stage, i.e. the feature of telogen rest stage normally, the hair follicle of degenerating in this stage contains the brood cell with the dermal papilla cell that compresses.In telogen, the startup of new hair early growth period is caused by the refining of the amplification of the fast breeding of brood cell's inner cell, dermal papilla and basement membrane component.This cycle repeats in the process of hair growth.When hair growth stopped, most of hair follicle was in telogen and do not enter the anagen, thereby caused the generation of all or part of alopecia.

Many records of attempting to cause hair regeneration length have been arranged in the literature, realized the anagen of for example attempting by promotion or prolongation.At present, Food and Drug Administration of the United States Federal has ratified two kinds of medicines that are used for the treatment of male baldness: external minoxidil (minoxidil) is (by Pharmacia﹠amp; Upjohn sells with Rogaine ) and oral Fei Nasi carry (finasteride) (by Merck; Co., Inc. sells with Propecia ).

But, have the ability that makes hair growth about minoxidil, the report of two kinds of mutual contradictions is arranged.In fact, be a kind of side effect by using the early stage clinical research that minoxidil brings high blood pressure down even not mentioning hirsutism (hair growth).Referring to, people such as Dormois, " minoxidil in the serious hypertension: the value of doing the time spent when the conventional medicine unable to get up ", American Heart Journal, the 90th volume, 360-368 page or leaf (1975).Really, the manufacturer of minoxidil has reported and has used a minoxidil hair growth limited in a part of patient.Referring to, as Physician ' s Desk Reference , the 49th edition (1995), the 2580th page.And minoxidil has serious adverse, comprises vasodilation (it causes fluid to remain on around the heart and increases heart rate), dyspnea and weight increase.Physician ' s Desk Reference , the 49th edition (1995), the 2581st page.

And, although early stage indicator shows that Propecia  may be more effective than Rogaine , use the patient of Propecia  to experience limited hair growth.Referring to, The New England Journal ofMedicine, the 338th volume, the 9th phase, on February 26th, 1998.And Propecia  has serious potential side effect.Propecia  may cause sexual impotence, libido reduction, ejaculate volume reduction, breast tenderness and increase and allergy, comprises lip swelling and skin rash.And women and child are instructed to use Propecia .In fact, the conceived or conceived women of possibility even should not dispose crushing or the broken tablet that contains this medicine.Referring to, Physician ' s Desk Reference , the 52nd edition (1998), the 1737th page and The New England Journal ofMedicine, the 338th volume, the 9th phase, on February 26th, 1998.

What is interesting is that known immunosuppressant cyclosporin A and FK506 can cause significant hirsutism side effect.Referring to, people such as Iwabuchi, " peptidyl-prolyl cis-trans isomerases of inhibitive ability of immunity (PPIase) inhibitor; cyclosporin A, FK506, ascosin (Ascomycin) and rapamycin (Rapamycin) influence initial to hair growth in the mice: the growth of new piliation does not need immunosuppressant ", Joumal ofDermatological Science, the 9th volume, 64-69 page or leaf (1995); People such as Yamamoto, " cyclosporin A and FK506, effective immunosuppressant, the effect of stimulating hair growth ", Journal ofDermatological Science, the 7th volume (supplementary issue), S47-S54 page or leaf (1994); People such as Yamamoto, " by local application FK506, effective immunosuppressant, stimulating hair growth ", Joumal ofInvestigational Dermatology, the 102nd volume, 160-164 page or leaf (1994); People such as Jiang, " by local application FK506, effective immunosuppressant is the anagen of inducing in the mouse skin of telogen ", Journal ofInvestigational Dermatology, the 104th volume, 523-525 page or leaf (1995); People such as McElwee, " local FK506: be used for the effective immunization therapy of alopecia bunch (AlopeciaAreata)? use Dundee to test the research of bald mouse model ", British Journal ofDermatology, the 137th volume, 491-497 page or leaf (1997); People such as Maurer, " regulating hair growth ", American Joumal of Pathology, the 150th volume, the 4th phase, 1433-1441 (1997) by local immunophilin part; With people such as Paus, " by immunosuppressant control hair growth ", Arch.Dermatol.Res., the 288th volume, 408-410 page or leaf (1996).But, because these chemical compounds as the remarkable effectiveness of immunosuppressant, may not be ideal so they are used as the hair growth active substance.

FK506 is the complicated macrocycle molecule with following array structure:

People such as Stocks, and " the excision of FK-506 in conjunction with the territory in in conjunction with the substituent contribution of pyranoside ", Bioorganic ﹠amp; Medicinal Chemistry Letters, the 4th volume, the 12nd phase, the 1,457 one 1460 page (1994).Disclose and had the very similar analog that should the complexity macro ring that the hair growth performance is for example alopecia bunch and/or male baldness form.Referring to, as people such as Kawai, US5,541,193, transfer Abbott Laboratories, on July 30th, 1996 authorized; People such as Asakura, US5,496,564, transfer Fujisawa Pharmaceutical Co., on March 5th, 1996 authorized; People such as Baumann, US5,352,671, transfer Sandoz Ltd., authorized on October 4th, 1994 and people such as Rupprecht, US5,550,233, transfer Merck; Co., Inc., on August 27th, 1996 authorized.

But, relate to the active excitement of hirsutism of cyclosporin A and FK506, to a certain extent, calmed down not as the shortage of the report of the immunosuppressant of littler, the non-macro ring FK506 complexity, various and non-immunosuppressive compounds hirsutism by relevant structure.Referring to, people such as Steiner, WO96/40140 transfers Guilford Pharmaceuticals, Inc., December disclosed on the 19th in 1996; People such as Hamilton, WO96/40633 transfers Guilford Pharmaceuticals, Inc., December disclosed on the 19th in 1996; People such as Steiner, US 5,696,135, transfer GPI NIL Holdings, Inc., December was authorized on the 9th in 1997; People such as Hamilton, US 5,614,547, transfer Guilford Pharmaceuticals, Inc, on March 25th, 1997 is open; People such as Steiner, WO97/16190 transfers GuilfordPharmaceuticals, Inc., on May 9th, 1997 is open; People such as Zelle, WO96/36630 transfers Vertex Pharmaceuticals, Inc., on November 21st, 1996 is open; People such as Armistead, WO97/36869 transfers Vertex Pharmaceuticals, Inc., on October 9th, 1997 is open; People such as Zelle, WO96/15101 transfers Vertex Pharmaceuticals, Inc., on May 23rd, 1996 is open; People such as Armistead, WO92/19593 transfers Vertex Pharmaceuticals, Inc., on November 1st 2,1992 is open; People such as Arimistead, WO94/07858 transfers VertexPharmaceuticals, Inc., on April 14th, 1994 is open; People such as Zelle, WO95/26337 transfers Vertex Phannaceuticals, Inc., October 5 nineteen ninety-five is open; People such as Duffy, WO92/21313 transfers Vertex Pharmaceuticals, Inc., December disclosed on the 10th in 1992; People such as Armistead, US 5,192,773, transfer Vertex Pharmaceuticals, Inc., on March 9th, 1993 is open; People such as Armistead, US 5,330,993, transfer Vertex Pharmaceuticals, Inc., on July 19th, 1994 authorized; People such as Arrnistead, US 5,622,970, transfer VertexPharmaceuticals, Inc., on April 22nd, 1997 authorized; People such as Armistead, US 5,654,332, transfer Vertex Pharmaceuticals, Inc., on August 5th, 1997 authorized; People such as Armistead, US 5,620,971, transfer Vertex Pharmaceuticals, Inc., on April 15th, 1997 authorized; People such as Zelle, US 5,543,423, transfer Vertex Pharmaceuticals, Inc., on August 6th, 1996 authorized; People such as Armistead, US 5,516,797, transfer Vertex Pharmaceuticals, Inc., on May 14th, 1996 authorized; People such as Armistead, US 5,665,774, transfer Vertex Pharmaceuticals, Inc., JIUYUE was authorized on the 9th in 1997; People such as Andres, " analog that the conformation of prolineamide limits, trans prolyl peptide mimicry ", Journal of Organic Chemistry, the 58th volume, 6609-6613 page or leaf (1993); With people such as Armistead, " design of the non-macrocyclic hcv inhibitors of FKBP12, synthetic and structure are used for the mainly conjugated protein of immunosuppressant FK506 ", ActaCrystallographica, D51,522-528 page or leaf (1995).

Surprisingly, the present inventor has had been found that the chemical compound of a class, its prevention and/or reverse hair loss or promotion hair growth, but the macrocyclic structure that does not have the complexity of FK506.The present inventor has further found to cause hair growth in this compounds but has been chemical compound non-inhibitive ability of immunity or that have small inhibitive ability of immunity astoundingly.Compare the reduction of the immunosuppressive activity of these hirsutism chemical compounds and/or to lack be tangible benefit with FK506 with the immunosuppressive compounds cyclosporin A.Therefore, the present inventor comprises that by administration the compound compositions that the present invention describes provides the method for the treatment of alopecia.

Summary of the invention

The present invention relates to be used for the treatment of the method for alopecia, the method of described treatment alopecia comprises the chemical compound that is specially adapted to treat the mammal alopecia that the administration inventor finds, the alopecia of described treatment mammal comprises prevention and/or reverse hair loss and promotes hair growth.The chemical compound that is used for the inventive method has following array structure:

But and the amide of pharmaceutically useful salt, hydrate and biological hydrolysis, ester and inferior amide, wherein substituent group G, J, K, A, B, D are as defined herein.

Detailed Description Of The Invention

The present invention relates to use the chemical compound and the method for compositions that are specially adapted to treat the mammal alopecia, the alopecia of described treatment mammal comprises prevention and/or reverse hair loss and promotes hair growth.

Except finding that chemical compound of the present invention can be used for treating the alopecia, the present inventor also is surprised to find to stimulate for hair growth does not need immunosuppressant.The present inventor has further found to be used for the treatment of alopecia but has been the chemical compound of non-inhibitive ability of immunity astoundingly.Therefore, preferred compound of the present invention, defined herein those are non-inhibitive abilities of immunity.

Open file and patent in the full text of present disclosure with for referencial use.Be incorporated herein all reference papers of being quoted as a reference.

Except as otherwise noted, all percents used herein, ratio and ratio all are weight ratios.

The definition of term and use

Hereinafter be the definition of term used herein:

Term used herein " salt " is the cationic salts that go up to form at any acidic-group (as carboxyl), or goes up the anion salt that forms at any basic group (as, amino).Many in this class salt are well known in the art.Preferred cation salt comprise alkali metal salt (as, sodium salt and potassium salt), alkali salt (as magnesium salt and calcium salt) and organic salt.Preferred anionic surfactants salt comprises halogenide (as villaumite).When administration, the acceptable salt of this class must be applicable to the mammal use.

Term used herein " alkenyl " is undersaturated hydrocarbon chain residue.Alkenyl has an olefinic double bond at least.Unless specialize, alkenyl has 2 to about 15 carbon atom (C ₂-C ₁₅), preferred 2 to about 10 carbon atom (C ₂-C ₁₀), more preferably 2 to about 8 carbon atom (C ₂-C ₈) and most preferably from about 2 to about 6 carbon atom (C ₂-C ₆).The non-limiting instance of alkenyl comprises vinyl, pi-allyl and cyclobutenyl.

Term used herein " oxyl (alkoxy) " has alkyl, alkenyl or alkynyl, and preferred alkyl or alkenyl most preferably are the oxygen residues of alkyl substituent.The example of oxyl residue comprises-the O-alkyl and-the O-alkenyl.

Term used herein " alkyl " is saturated hydrocarbon chain residue.Unless specialize, alkyl has 1 to about 15 carbon atom (C ₁-C ₁₅), preferred 1 to about 10 carbon atom (C ₁-C ₁₀), more preferably 1 to about 6 carbon atom (C ₁-C ₆); Most preferably from about 1 to about 4 carbon atom (C ₁-C ₄).Preferred alkyl for example comprises methyl, ethyl, propyl group, isopropyl and butyl.

Term used herein " alkylene (allkylene) " refers to alkyl, alkenyl or alkynyl for two residues (diradical).For example, " methylene " is-CH ₂-.

Term used herein " alkynyl " is undersaturated hydrocarbon chain residue.Alkynyl has a triple bond at least.Unless specialize, alkynyl has 2 to about 15 carbon atom (C ₂-C ₁₅), preferred 2 to about 10 carbon atom (C ₂-C ₁₀), more preferably 2 to about 8 carbon atom (C ₂-C ₈) and most preferably from about 2 to about 6 carbon atom (C ₂-C ₆).

Term used herein " but amide of biological hydrolysis " is the amide that is used for chemical compound of the present invention that does not disturb described compound activity or changed into reactive compound easily in the mammal main body body.

Term used herein " but ester of biological hydrolysis " is the ester that is used for chemical compound of the present invention that does not disturb described compound activity or changed into reactive compound easily in the mammal main body body.

Term used herein " but inferior amide of biological hydrolysis " is the inferior amide that is used for chemical compound of the present invention that does not disturb described compound activity or changed into reactive compound easily in the mammal main body body.

Term used herein " carbocyclic ring " or similar terms are hydrocarbon ring residues.Carbocyclic ring is that monocycle or fused rings, bridging ring or spiral shell are multi-ring.Unless specialize, monocycle contain 3 to about 9 atoms, preferred about 4 to about 7 atoms, 5 or 6 atoms most preferably.Multi-ring contain have an appointment 7 to about 17 atoms, preferred about 7 to about 14 atoms, 9 or 10 atoms most preferably from about.

Term used herein " cycloalkyl " is saturated carbocyclic ring or heterocycle residue.Preferred cycloalkyl comprises for example cyclobutyl, cyclopenta and cyclohexyl.

Term used herein " heterochain thiazolinyl " is to contain carbon atom and one or more heteroatomic alkenyl residue at the alkenyl chain, and wherein hetero atom is selected from oxygen, sulfur, nitrogen and phosphorus, is more preferably oxygen, sulfur and nitrogen.

Term used herein " assorted alkyl " is to contain carbon atom and one or more heteroatomic alkyl residue at alkyl chain, and wherein hetero atom is selected from oxygen, sulfur, nitrogen and phosphorus, is more preferably oxygen, sulfur and nitrogen.

Term used herein " heterocycle " or similar terms are the ring residues that is made of intra-annular carbon atom and one or more hetero atom, and wherein hetero atom is selected from oxygen, sulfur, nitrogen and phosphorus, are more preferably oxygen, sulfur and nitrogen.Heterocycle is that monocycle or fused rings, bridged ring or spiral shell are multi-ring.Unless specialize, monocycle contain 3 to about 9 atoms, preferred about 4 to about 7 atoms, 5 or 6 atoms most preferably.Multi-ring contain have an appointment 7 to about 17 atoms, preferred about 7 to about 14 atoms, 9 or 10 atoms most preferably from about.Heterocycle can be that replace or unsubstituted.

Term used herein " rudimentary " partly (as " rudimentary " alkyl) is to have 1 to about 6, preferred 1 part to about 4 carbon atoms.

Term used herein " pharmaceutically useful " refers to be applicable to the mankind or other mammal.

Term used herein " chemical compound of safe and effective amount " (or compositions etc.) refers to present bioactive effective dose, preferred biological activity wherein is active site prevention and/or the reverse hair loss in the mammal main body and promotes hair growth, and do not have adverse side effect (as toxicity, stimulation or anaphylaxis) improperly, when being used for method of the present invention, consider rational terrible ratio.

Just as used herein, when any variable in any variable or structure, partly, occurrence number such as group is during more than one time, its definition when its definition is independent of another time and occurs at every turn when occurring.

Method of the present invention

The present invention relates to treat the method for alopecia, comprise that described compositions comprises to a kind of compositions of clothes:

(a) have the chemical compound of following array structure:

But and the amide of pharmaceutically useful salt, hydrate and biological hydrolysis, ester and inferior amide, wherein:

(ⅰ) Q is first hetero atom, and wherein first hetero atom is a nitrogen;

(ⅱ) G is selected from C ₁-C ₆Alkyl, C ₁-C ₆Alkenyl, C ₅-C ₇Cycloalkyl, C ₁-C ₄The C that alkyl replaces ₅-C ₇Cycloalkenyl, C ₂-C ₄The C that alkenyl replaces ₅-C ₇Ar and Ar that the Ar that cycloalkenyl, alkyl replace, alkenyl replace;

(ⅲ) Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, piperazinyl, piperidyl, monocyclic heterocycles and bicyclic heterocycle, and wherein Ar randomly is selected from following substituent group independently of one another and replaces by one or more: hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₁-C ₄Alkoxyl, benzyloxy, phenoxy group, 1,2-methylene-dioxy, amino, carboxyl and phenyl;

(ⅳ) J is selected from hydrogen, C ₁-C ₂Alkyl and benzyl; K is selected from C ₁-C ₄Alkyl, benzyl and cyclohexyl methyl; Or J and K can be joined together to form 5-, 6-or 7-unit heterocycle, and wherein this ring can randomly comprise and is selected from O, S, S (O), S (O ₂) other hetero atom;

(ⅴ) A is selected from CH ₂, O, NR ₁, R wherein ₁Be selected from hydrogen and C ₁-C ₄Alkyl;

(ⅵ) B and D are selected from hydrogen, Ar, C independently of one another ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Alkyl, C ₅-C ₇The C of cycloalkyl substituted ₂-C ₆Alkenyl, C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₂-C ₆Alkenyl, C ₁-C ₆Ar, C that alkyl replaces ₁-C ₆Ar, C that alkenyl replaces ₁-C ₆Assorted alkyl, C ₂-C ₆Heterochain thiazolinyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Assorted alkyl, C ₅-C ₇The C of cycloalkyl substituted ₂-C ₆Heterochain thiazolinyl, C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Assorted alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₂-C ₆Heterochain thiazolinyl, C ₁-C ₆Ar, C that assorted alkyl replaces ₂-C ₆The Ar of heterochain alkenyl substituted, and

Wherein Z is selected from hydrogen, C ₁-C ₆Alkyl and C ₂-C ₆Alkenyl, and wherein T is selected from Ar and 5-, 6-or 7-unit cycloalkyl, and it is selected from hydrogen, hydroxyl, C ₁-C ₄At least one substituent group of alkoxyl and oxo replaces; Wherein at least one among B and the D is not hydrogen; And

(ⅶ) m is 0 to 3 integer; And

(b) pharmaceutically useful carrier.

The G part

The G part directly partly links to each other with sulfonamide, as shown in the present.Preferred G partly comprises and replacing or unsubstituted phenyl, 4-aminomethyl phenyl, 2-thienyl, 2,4,6-triisopropyl phenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N, the N-dimethylamino) naphthyl, 4-methoxyphenyl, 4-iodine substituted phenyl, 2,4,6-trimethylphenyl, benzyl, 2-naphthyl, 4-nitrobenzophenone, 3-nitrobenzophenone, 4-chlorophenyl and E-styryl.Most preferred G partly is 3,4, the 5-trimethoxyphenyl.

J and K part

J and K part can have aforesaid structure independently of each other, perhaps can be joined together to form 5-, 6-or 7-unit heterocycle as mentioned above, and this heterocycle randomly contains other and is selected from O, S, S (O) and S (O) ₂Hetero atom.Preferably, J and K are joined together to form and randomly contain other and be selected from O, S, S (O) and S (O) ₂Heteroatomic 5-, 6-or 7-unit heterocycle.When J and K formation heterocycle, this encircles preferably 5-or 6-unit ring.When J and K formation heterocycle, this heterocycle does not contain any other hetero atom at the required non-Q nitrogen in the 1-position of this ring, and is as described herein.

The A part

A is selected from CH ₂, O and NR ₁, R wherein ₁Be selected from hydrogen and C ₁-C ₄Alkyl.Preferably, A is selected from O and NR ₁Most preferably, A is NR ₁R ₁Most preferably be hydrogen.

R and D side chain

B and D are side chains, are selected from various aforesaid parts.

Preferred B partly is selected from hydrogen, C ₁-C ₆Alkyl, C ₁-C ₆Alkenyl, 3-(2-pyridine radicals) propyl group, the 3-phenyl propyl, the 2-phenoxy propyl, the 3-Phenoxyphenyl, phenyl, benzyl, 2-(3-pyridine radicals) ethyl, E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl, E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-second-2-thiazolinyl, 3-(3-pyridine radicals) propyl group, the 2-phenylethyl, 2-(4-methoxyphenyl) ethyl, 3-(N-benzimidazolyl) propyl group, 3-(4-methoxyphenyl) ethyl, 3-[N-(7-azaindolyl)] propyl group, 3-(N-purine radicals) propyl group, 3-(3-pyridine radicals)-N-oxide, 3-(4-hydroxymethyl phenyl) propyl group, 3-(2-thienyl) propyl group, 3-(4-carboxyl phenyl) propyl group, the 4-phenyl methyl, the 2-hydroxymethyl phenyl, 2-pi-allyl oxygen phenyl, 3-(3-hydroxymethyl phenyl) propyl group, 3-(3-carboxyl phenyl) propyl group, the 3-hydroxymethyl phenyl, the 2-hydroxy phenyl, the 3-pyridine radicals, the 5-phenylpentyl, 4-(4-methoxyphenyl) butyl, 4-cyclohexyl butyl, 3-cyclohexyl propyl group, 3-cyclopenta propyl group, 3-phenoxy benzyl and 3-(3-indyl) propyl group.

Preferred D partly is selected from zero, hydrogen, 3-phenyl propyl, 2-Phenoxyphenyl, 3-(3-indyl)-propyl group, 2-phenylethyl, 4-phenyl butyl, 3, two (benzyloxy) phenyl of 5-, C ₁-C ₆Alkyl, C ₁-C ₆Alkenyl, phenyl and 3-(methoxyphenyl) propyl group.

Integer m

Integer m is 0 to 3, is preferably 0 to 1.

The chemical compound that preferably is used for the inventive method is shown in the following table:

????B	????D	????G
			Hydrogen	Phenyl	Phenyl
Hydrogen	Phenyl	The 4-aminomethyl phenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3,4 dimethyl hydrogen-based phenyl

Table 2

????B	????D	????G
			Hydrogen	Phenyl	Phenyl
Hydrogen	Phenyl	The 4-aminomethyl phenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3, the 4-Dimethoxyphenyl

Table 3

????B	????D	????G
			Hydrogen	Phenyl	The 4-aminomethyl phenyl
Hydrogen	The 3-phenyl propyl	The 4-aminomethyl phenyl
			Hydrogen	The 3-phenyl propyl	The 4-methoxyphenyl
Hydrogen	The 3-phenyl propyl	The 2-thienyl
			Hydrogen	The 3-phenyl propyl	2,4,6-triisopropyl phenyl
Hydrogen	The 3-phenyl propyl	The 4-fluorophenyl
			Hydrogen	The 3-phenyl propyl	Phenyl
Hydrogen	The 3-phenyl propyl	The 3-methoxyphenyl
			Hydrogen	The 3-phenyl propyl	The 2-methoxyphenyl

Hydrogen	The 3-phenyl propyl	3,5 Dimethoxyphenyls
			Hydrogen	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Hydrogen	The 3-phenyl propyl	Methyl
			Hydrogen	The 3-phenyl propyl	The 8-quinolyl
Hydrogen	The 3-phenyl propyl	1-(5-N, N-dimethylamino) naphthyl
			Hydrogen	The 4-Phenoxyphenyl	The 4-methoxyphenyl
Hydrogen	The 4-Phenoxyphenyl	The 5-aminomethyl phenyl
			Hydrogen	The 3-Phenoxyphenyl	The 2-thienyl
Hydrogen	The 3-Phenoxyphenyl	The 8-quinolyl
			Hydrogen	The 3-Phenoxyphenyl	The 4-iodine substituted phenyl
Hydrogen	The 3-Phenoxyphenyl	2,4, the 6-trimethylphenyl
			Hydrogen	The 3-Phenoxyphenyl	Benzyl
Hydrogen	The 3-Phenoxyphenyl	The 2-naphthyl
			Benzyl	The 3-phenyl propyl	The 4-fluorophenyl
The 2-phenylethyl	The 3-phenyl propyl	The 4-fluorophenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 4-aminomethyl phenyl
The 3-phenyl propyl	The 3-phenyl propyl	The 4-nitrobenzophenone
			The 3-phenyl propyl	The 3-phenyl propyl	The 3-nitrobenzophenone
The 3-phenyl propyl	The 3-phenyl propyl	The 4-chlorphenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 4-methoxyphenyl
The 3-phenyl propyl	The 3-phenyl propyl	The 4-fluorophenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 2-thienyl
Hydrogen	The 3-phenyl propyl	The E-styryl
			Benzyl	Phenyl	The 2-ethylphenyl
Benzyl	Hydrogen-	2-ethyl (3-4-5-trimethoxy) phenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3, the 4-Dimethoxyphenyl

Table 4

????B	????D	????G
			Hydrogen	Phenyl	The 4-aminomethyl phenyl
Hydrogen	The 3-phenyl propyl	The 4-aminomethyl phenyl
			Hydrogen	The 3-phenyl propyl	The 4-methoxyphenyl
Hydrogen	The 3-phenyl propyl	The 2-thienyl
			Hydrogen	The 3-phenyl propyl	2,4,6-triisopropyl phenyl
Hydrogen	The 3-phenyl propyl	The 4-fluorophenyl
			Hydrogen	The 3-phenyl propyl	Phenyl
Hydrogen	The 3-phenyl propyl	The 3-methoxyphenyl
			Hydrogen	The 3-phenyl propyl	The 2-methoxyphenyl
Hydrogen	The 3-phenyl propyl	3, the 5-Dimethoxyphenyl
			Hydrogen	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Hydrogen	The 3-phenyl propyl	Methyl
			Hydrogen	The 3-phenyl propyl	The 8-quinolyl
Hydrogen	The 3-phenyl propyl	1-(5-N, N-dimethylamino) naphthyl
			Hydrogen	The 4-Phenoxyphenyl	The 4-methoxyphenyl
Hydrogen	The 4-Phenoxyphenyl	The 5-aminomethyl phenyl
			Hydrogen	The 3-Phenoxyphenyl	The 2-thienyl
Hydrogen	The 3-Phenoxyphenyl	The 8-quinolyl
			Hydrogen	The 3-Phenoxyphenyl	The 4-iodine substituted phenyl
Hydrogen	The 3-Phenoxyphenyl	2,4, the 6-trimethylphenyl
			Hydrogen	The 3-Phenoxyphenyl	Benzyl
Hydrogen	The 3-Phenoxyphenyl	The 2-naphthyl
			Benzyl	The 3-phenyl propyl	The 4-fluorophenyl
The 2-phenylethyl	The 3-phenyl propyl	The 4-fluorophenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 4-aminomethyl phenyl
The 3-phenyl propyl	The 3-phenyl propyl	The 4-nitrobenzophenone
			The 3-phenyl propyl	The 3-phenyl propyl	The 3-nitrobenzophenone
The 3-phenyl propyl	The 3-phenyl propyl	The 4-chlorphenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 4-methoxyphenyl

The 3-phenyl propyl	The 3-phenyl propyl	The 4-fluorophenyl
			The 3-phenyl propyl	The 3-phenyl propyl	The 2-thienyl
Hydrogen	The 3-phenyl propyl	The E-styryl
			Benzyl	Phenyl	The 2-ethylphenyl
Benzyl	Hydrogen	2-ethyl (3,4, the 5-trimethoxy) phenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3, the 4-Dimethoxyphenyl

Analytical method

The present invention relates to treat the method for alopecia by the chemical compound that administration has a structure of the present invention.In these chemical compounds, preferred chemical compound is non-inhibitive ability of immunity.Can use the ability of following method test compounds (test compounds) anagen of inducing and its immunosuppressive activity (or its shortage).Perhaps, can use other method well known in the art (still, term " nonimmunosuppressive " defines according to method disclosed herein).

Telogen transition detection

Transition detection telogen (Telogen Conversion Assay) is measured, and to be test compounds with the hair of mice the potential of the growth stage that macrocyclic rest stage converts (" telogen ") growth cycle of hair to (" anagen ") takes place.

Be not wishing to be bound by theory, growth cycle of hair has three Main Stage: the anagen, catagen and telogen.Believe that (Indianapolis IN) has long telogen to the C3H mouse in about 40 day age to about 75 day age for Harlan Sprague Dawley, Inc., and this moment, hair growth existed simultaneously.Believe that after 75 day age, hair growth occurs no longer simultaneously.During have the black fur when in hair growth experiment, the using mice in about 40 day age of (palm fibre or black), follow hair (fur) growth melanogen to occur and generate, wherein assess the hair growth promoter of local application.Use transition detection telogen hereinafter generates by the measurement melanogen screens the chemical compound with hair growth potentiality.

Use the C3H mouse in three groups of 44 day ages: media (vehicle) matched group, positive controls and test compounds group, what wherein the test compounds group was given clothes is the chemical compound that is used for the inventive method.Detection period was at least 19 days, and 15 treatments day (wherein treatment day is Mon-Fri) are wherein arranged.First day is first day of treatment.Most of researchs will finish at the 19th day, if but melanogen generates response looks to be positive but when carrying out slowly, some researchs will proceed to the 24th day so.Typical research design has been shown in the following table 5:

Table 5

Group number	Number of animals	Chemical compound	Concentration	Amount of application	The research phase
						1	?1-10	Test compounds	5%, at media **In	400 microlitres, the part	19 or 24 days
2	?11-20	Cyclosporin A	0.19%, at media **In	400 microlitres, the part	19 or 24 days
						3	?21-30	Media **	Do not analyze	400 microlitres, the part	19 or 24 days

^*Media be 60% ethanol, 20% propylene glycol and 20% different sorbic acid dimethyl ester (available from Sigma Chemical Co., St.Louis, MO).

In back of the body bottom (at the bottom of afterbody, extremely descending rib) it is carried out topical therapeutic from Mon-Fri to mice.Use pipet and tube head (tip) 400 microlitres to be moved to the back of each mice.Use 400 microlitre amounts of application lentamente, the hair on the mobile simultaneously mice makes uses arrival skin.

When local application on mice is handled at every turn, the skin color in the application zone of each animal is provided the range estimation rank of 0-4.In the time of the anagen that mice converted to from telogen, its skin color will become more bluish black.As shown in table 6 below, when skin is become when black-and-blue by white, the following visual observations result of rank 0 to 4 representative:

Table 6

Visual observations result	Rank
		Shallow white skin color	????0
Skin is light grey (beginning the anagen of expression)	????1
		Blue spot appears	????2
The blue spot accumulation forms a BigBlue zone	????3
		Skin is black and blue color (almost being black), and the major part of area for treatment is covered (expression mice anagen phase) completely by color	????4

Immunosuppressant detects

The immunosuppressant of this paper detects the immunosuppressive activity of having predicted the chemical compound that is used for the inventive method.The following detection:

Dead (the CO of the peace in from 7 to 16 ages in week ₂Suffocate) bull C3H mouse (mice that lives can be from Harlan Sprague Dawley, Inc., Indianapolis, IN has bought) excision spleen.With spleen be placed on immediately cold Hanks Balanced Salt Solution (HBSS, available from Gibco-BRL, Gaithersburg, MD) in.Then, spleen is ground between freezing glass slide, and filter to remove fragment of tissue by aseptic screen cloth.With the cell suspending liquid of gained be placed on isopyknic Ficoll-Paque Plus (available from Pharmacia Biotech, Piscataway, NJ) following and under 400 * g 20 ℃ centrifugal about 40 minutes to collect splenocyte.Use disposable pipet from collecting splenocyte at the interface, and use the HBSS washed twice, then under 100 * g 20 ℃ centrifugal 10 minutes down.Splenocyte is resuspended in 5 to the 10 ml cells culture medium, this cell culture medium constitutes (cell culture medium of having bought from Gibco-BRL) by the red RPMl1640 of reactive phenol, and it contains 10% heat-inactivated hyclone (Gibco-BRL), penicillin (50U/ml), streptomycin (100 mcg/ml), L-glutaminate (2mM), 2 mercapto ethanol (10 ^-5M) and the N-2-hydroxyethyl piperazine-N ＇-2-ethanesulfonic acid (HEPES) (10mM).Use and count and check its viability as the trypan blue pair cell.With splenocyte with 10 ⁶Cells/ml is resuspended in the culture medium and with 10 ⁵Cells/well moves in the round bottom plate in 96 holes.By adding 50 microlitres/hole concanavalin A (conconavalin A) (final detectable concentration is 5 mcg/ml) splenocyte is activated in the existence of test compounds or not.Test compounds is made for stock solution in the dimethyl sulfoxide (DMSO), and dilution and add with 50 microlitres/hole in culture medium then makes the ultimate density that detects DMSO in the liquid be lower than 0.05%.At 37 ℃ at 5%CO ₂Down plate was cultivated 48 hours.After 48 hours, with cell with the methyl in 1 μ Ci/ hole- ³(available from Amersham, Buckinghamshire England) adds pulse and also cultivated 24 hours again the H-thymidine.

After 24 hours, with cell harvesting the GF/C screen plate (available from Packard, Downers Grove, IL) on, be dissolved among the Microscint 20 (Packard), and on the TopCount microtest plate glimmers luminous board-like enumerator (Packard), count.Measure the activity of the active percent of thing in contrast under the test compounds not existing, and with respect to the concentration mapping of test compounds.Data are applied to the 4-parameter curve to be cooperated (Sigmaplot) and calculates IC ₅₀Value.Just as used herein, if use this method, (cyclosporin A IC ₅₀/ test compounds IC ₅₀) ratio * 100 be less than or equal to 0.02, the immunosuppressive activity of promptly non-immunosuppressant test compounds thinks so that less than 2% of cyclosporin A this test compounds is non-inhibitive ability of immunity.

(3-［ 4 to use MTT, 5-dimethyl-thiazolyl-2-yl] 2,5-diphenyl-tetrazolium bromide) dyestuff detects the assessment cell survival, described as people such as Nelson, Journal of Immunology, the 150th volume, the 6th phase, 2139-2147 page or leaf (1993), difference is that described detection is at serum-free, carry out among the red RPMI1640 of reactive phenol, and dyestuff is dissolved among 100 microlitres/hole DMSO, at SpectraMax Plus microtest plate readout instrument (Molecular Devices, Menlo Park CA) is upward carrying out reading under the optical density of 540 nanometers under the background correction of 650 nanometers.

Preparation method

The chemical compound that is used for the inventive method according to method preparation known to a person of ordinary skill in the art.The initial substance that is used to prepare these chemical compounds is known, by the known method preparation, or can buy from the market as initial substance.

Will be appreciated that the those of ordinary skill of organic chemistry filed can carry out the standard operation of organic compound easily, and does not need further indication.The example of this generic operation is at standard article such as J.March, Advanced Organic Chemisty, John Wiley ﹠amp; Sons discusses in 1992.

Those of ordinary skill is understood easily, at last when sheltering or protecting other functional group in the chemical compound, carries out some reaction, thereby increases reaction yield and/or avoid unwanted side reaction.Those of ordinary skill uses blocking group to realize the increase of this class productive rate usually or avoids unwanted reaction.These reactions are described and in the literature also within the scope of those of ordinary skill.Some examples of this generic operation can see as T.Greene, Protecting Groups in Organic Synthesis, John Wiley ﹠amp; Sons, 1981.

Chemical compound of the present invention can have one or more chiral centres.The result is, people can be better than another kind of optical isomer and optionally prepare a kind of optical isomer, comprise diastereomer and enantiomer, for example obtain by chirality initial substance, catalyst or solvent, or can once prepare two kinds of stereoisomers or two kinds of optical isomers simultaneously, comprise diastereomer and enantiomer (racemic mixture).Because can be used as racemic mixture, chemical compound of the present invention exists, so can use known method, as by using mixture as chirality salt and chiral chromatogram separating optical isomers, comprise diastereomer and enantiomer, or stereoisomer.

In addition, will be appreciated that a kind of optical isomer comprises diastereomer and enantiomer, or stereoisomer, can have favorable properties than another kind of optical isomer.Therefore, when open and protection is of the present invention, when disclosing a kind of racemic mixture, obviously plan also to disclose and protect two kinds of optical isomers simultaneously, comprise diastereomer and enantiomer, or be substantially free of the stereoisomer of other material.

Hereinafter provide non-limiting instance to be described more specifically the method for preparation all cpds of the present invention.

This paper uses following abbreviation:

Reagent	Abbreviation
		N, dinethylformamide	DMF
The I-hydroxybenzotriazole hydrate	HOBt
		Tert-butoxycarbonyl	BOC

(benzotriazole-1-base oxygen) tripyrrole alkyl phosphorus hexafluorophosphate is (available from Fluka Chemical, Switzerland)	PyBOP
		Oxolane	THF
N, the N-diisopropyl ethyl amine	i-Pr 2NEt or i-Pr 2EtN
		Trifluoroacetic acid	TFA

Embodiment 1

1a. (S)-3-phenyl butyl pipecolinic acid ester: at tartrate (5.0 grams of (S)-pipecolinic acid, 17.9 add 4-phenyl-1-butanols (13.8 grams in the slurry of 50 milliliters of dried benzene mM), 89.5 mM) and the p-methyl benzenesulfonic acid monohydrate (3.8 the gram, 19.8 mM), the mixture of gained reflux under Dean Stark trap is spent the night.Concentrate gained solution, be dissolved in 100 milliliters of ethers of 4: 1: in the ethyl acetate, with the hydrochloric acid extraction of 0.5N.Tart water-bearing layer is with 100 milliliters of ethers of 4: 1: the ethyl acetate washing by adding 8 milliliters 30% ammonium hydroxide alkalization, is extracted in the ethyl acetate.With the organic extract salt water washing that merges, use dried over mgso, concentrate and obtain free amine.

1b. (S)-and 3-phenyl butyl N-(4-methyl sulphonyl)-pipecolinic acid ester: in the solution of amine 1a (30 milligrams, 0.12 mM) in 0.5 milliliter of dichloromethane, add i-Pr ₂EtN (22 microlitres, 0.13 mM) and paratoluensulfonyl chloride (24 milligrams, 0.13 mM).The mixture of gained at room temperature stirred 1 hour.Concentrated reaction mixture obtains required sulfonamide through chromatography.

Example 2

2a.4-phenyl-1-butyraldehyde: at 0 ℃, in the solution of 20 milliliters of dichloromethane, add the 3A molecular sieve (3.2 gram) of powdered to 4-phenyl-1-butanols (3.2 milliliters, 20.8 mMs), then add pyridinium chlorochromate father-in-law (PCC) (5.37 grams, 24.9 mMs).The suspension of gained was stirring 1 hour at 0 ℃, added PCC (2.16 grams, 10 mMs) in this process once more.The reacting by heating mixture is to room temperature.Stir after 0.5 hour, use the ether diluted reaction mixture,, obtain crude product by diatomite filtration.

2b.3-phenyl-1-propyl group magnesium chloride: at room temperature to (736 milligrams of magnesium recycle, 30.3 mM) in the suspension of THF (50 milliliters), add 1,2-Bromofume (50 microlitre) next dropwise adds 1-bromo-3-phenyl-propane (5.5 grams, 25.1 mMs).After at room temperature stirring 0.5 hour, supernatant is transferred in the accumulator tank (100 milliliters), next is used as the THF solution of the Grignard reagent of 0.5M by sleeve pipe.

2c.1,7-diphenyl-4-enanthol: under 0 ℃, in the solution of 4-phenyl-2-butyraldehyde (700 milligrams, 4.7 mMs) in THF (5.0 milliliters), add (10 milliliters of 3-phenyl-1-propyl group magnesium bromide, 5 mMs), the mixture with gained stirred 0.5 hour at 0 ℃.Make the mixture quenching by dropwise adding saturated ammonium chloride, and dilute with ether.Separate each phase, dried over mgso is used in organic layer water and salt water washing then.Concentrate and obtain required alcohol.

2d. (S)-Boc-2-piperidines acyl group-1; 7-diphenyl-4-heptyl ester: at room temperature; to (164 milligrams of (S)-Boc-L-2-nipecotic acids; 0.72 mM) in the solution in 5 milliliters of dichloromethane; add (174 milligrams of pure 2c; 0.65 mM), the N of EDAC (140 milligrams, 0.72 mM) and catalytic amount, N-dimethyl aminopyridine.At room temperature stirred reaction mixture is 0.5 hour, is applied directly on the silicagel column then.Eluting obtains required ester.

2e. (S)-1,7-diphenyl-4-heptyl pipecolinic acid ester: at room temperature, in the solution of ester 2c (47 milligrams, 0.10 mM) in 1 milliliter of dichloromethane, add TFA (1 milliliter).After at room temperature stirring 0.5 hour, dropwise add saturated potassium carbonate with in and the solution of gained.Separate each layer, organic facies washes with water, uses dried over mgso, obtains required product after concentrating.

2f. (S)-1,7-diphenyl-4-heptyl N-(4-methoxyl group sulfonyl)-pipecolinic acid ester: in the solution of dichloromethane (1 milliliter), add i-Pr to amine 2e (12.1 milligrams, 0.031 mM) ₂EtN (6 microlitres, 0.035 mM) and 4-methoxybenzene sulfonic acid chloride (7.1 milligrams, 0.034 mM).The mixture of gained was at room temperature stirred 1 hour.Concentrated reaction mixture obtains required sulfonamide by chromatograph.

Embodiment 3

3a. (S)-and (N-tertbutyloxycarbonyl)-pipecolinic acid ester 1,7-diphenyl-4-heptamide: (S)-(N-tertbutyloxycarbonyl)-pipecolinic acid (4.0 grams, 17.7 mMs) is dissolved among 160 milliliters of DMF.Add 1, amino heptane of 7-diphenyl-4-(4.30 grams, 16.1 mMs) and N, N-diisopropyl ethyl amine (4.16 grams, 32.2 mMs) next adds PyBOP (8.80 grams, 16.9 mMs).At room temperature reaction stirred is 18.5 hours, pours into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), extracts with ethyl acetate (600 milliliters).With saline (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and saline (2 * 200 milliliters) continuous washing.Use dried over mgso organic solution, filter concentrating under reduced pressure.With purifying products, obtain required amide 3a by silica gel chromatography.

3b. (S)-and pipecolinic acid 1,7-diphenyl-4-heptyl amide: amide 3a (7.3 grams, 15.3 mMs) is dissolved in 150 milliliters of anhydrous methylene chlorides.In 5 minutes, dropwise add trifluoroacetic acid (120 milliliters).After two hours, cooling mixture in ice bath adds the unsaturated carbonate potassium solution and is approximately till 8 until pH.Mixture is transferred in the separatory funnel that comprises dichloromethane (200 milliliters) and water (200 milliliters), rocks.After with dried over mgso, water (200 milliliters) washing organic layer.Filtering mixt, concentrating under reduced pressure obtain required amide 3b.

3c. (S)-and N-(3 ', 4 '-Dimethoxyphenyl sulfonyl)-pipecolinic acid 1,7-diphenyl-4-heptyl amide: at room temperature, amide 3b (4.4 grams, 11.7 mMs) is absorbed in the anhydrous methylene chloride (100 milliliters).Add N, N-diisopropylethylamine (2.55 milliliters, 14.7 mMs) is cooled to 5 ℃ with this solution.Once add 3 ', 4 '-Dimethoxyphenyl sulfonyl chlorine (3.47 grams, 14.7 mMs).At room temperature stirred reaction mixture is 18 hours, is concentrated to half volume then.Concentrate is poured on the ethyl acetate (300 milliliters), with 0.1M hydrochloric acid (100 milliliters), saturated sodium bicarbonate (100 milliliters) and the washing of saline (50 milliliters) order.The organic solution dried over mgso is filtered vacuum concentration.Preparation chromatogram purification crude product by on silica gel obtains required sulfonamide 3c.

Embodiment 4

(4a. N-tert-butoxycarbonyl)-pyrrolidine-2 (S)-carboxylic acid 1,7-diphenyl-4-heptyl amide: (N-tert-butoxycarbonyl)-pyrrolidine-2 (S)-carboxylic acid (3.8 grams, 17.7 mMs) is absorbed among 160 milliliters of DMF.Add 1, amino heptane of 7-diphenyl-4-(4.30 grams, 16.1 mMs) and N, N-diisopropylethylamine (4.16 grams, 32.2 mMs) then adds PyBOP (9.20 grams, 17.1 mMs) again.At room temperature reactant was stirred 20.5 hours, pour into then on the ice-cold 0.1N hydrochloric acid (600 milliliters), extract with ethyl acetate (600 milliliters).Separate each layer, with saline (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and the washing of saline (2 * 200 milliliters) order.The organic solution dried over mgso is filtered concentrating under reduced pressure.This product by silica gel purification, is obtained required amide 4a.

4b. pyrrolidine-2 (S)-carboxylic acid 1,7-diphenyl-4-heptyl amide: amide 4a (7.4 gram, 16.5 mMs) is absorbed in 160 milliliters the anhydrous methylene chloride.In 5 minutes, add trifluoroacetic acid (130 milliliters).After 45 minutes, mixture is cooled off in ice bath, add saturated potassium carbonate and be approximately 8 until pH.Mixture is transferred in the separatory funnel that contains dichloromethane (300 milliliters) and water (300 milliliters), rocks.Dried over mgso is used in organic layer water (100 milliliters) washing then.Filtering mixt, concentrating under reduced pressure obtains required amide 4b.

(4c.N-3 ', 4 '-Dimethoxyphenyl sulfonyl)-pyrrolidine-2 (S)-carboxylic acid 1,7-diphenyl-4-heptyl amide: at room temperature, amide 4b (4.38 grams, 12.0 mMs) is absorbed in the anhydrous methylene chloride (100 milliliters).Add N, N-diisopropylethylamine (2.6 milliliters, 15 mMs) is cooled to 5 ℃ with this solution.Once add 3 ', 4 '-Dimethoxyphenyl sulfonic acid chloride (3.5 grams, 15 mMs).At room temperature stirred reaction mixture is 18 hours, is concentrated to half volume then.Concentrate is poured on the ethyl acetate (300 milliliters), with 0.1M hydrochloric acid (100 milliliters), saturated sodium bicarbonate (100 milliliters) and the washing of saline (50 milliliters) order.Dry organic layer filters vacuum concentration.By preparation property chromatogram purification crude product, obtain required sulfonamide 4c.

Embodiment 5

5a. under agitation magnesium (40.2 grams, 1.65 moles) and absolute ether (3.2 liters) are incorporated in the reaction vessel.The solution of 1-bromo-3-phenyl-propane in 1.6 liters of absolute ethers is added in the charging hopper.During 1 hour, described bromide solution is added dropwise in the reaction vessel that is stirring.When reinforced finishing, mixture was stirred 1 to 2 hour.The solution of 4-phenylbutyronitrile (160 grams, 1.1 moles) in 2.4 liters of absolute ethers is put into charging hopper.During 1 hour, described drips of solution is added in the reaction vessel.When reinforced finishing, solution is heated to backflow 10 hours, at room temperature stir the solution that obtained 9a in 6 hours then.

5b.1, the amino heptane of 7-diphenyl-4-: use the reactant mixture of charging hopper with methanol (3.2 liters) dilution 5a.Add sodium borohydride (83.4 grams, 2.2 moles) several times.When reinforced finishing, reactant was at room temperature stirred 6 hours.Make the reactant mixture chilling by slowly adding entry (3.2 liters).Mixture dilutes with ether (3.2 liters) and water (1.6 liters).Separate the ether layer and use ether (3.2 liters * 2) the water-bearing layer extracting twice.With sodium chloride solution with the ether extract washing that merges once, drying is filtered and is carried out vacuum concentration and obtains thick product.This product is diluted in the ether (1.2 liters), and by slowly adding lM HCl (1.2 liters) acidify.Mixture was stirred 1 hour vacuum concentration.Gained precipitate dilution in acetonitrile, and restir 16 hours.Filter to collect required 1, the amino heptane 5b of 7-diphenyl-4-.

The purposes of The compounds of this invention

Method of the present invention is to be undertaken by chemical compound that has structure described herein to clothes and pharmaceutically useful carrier.

The chemical compound of this paper can be used for treating such disease, and as the mammal alopecia, the alopecia of described treatment mammal comprises inhibition and/or reverse hair loss and promotes hair growth.Such disease for example can show as, and alopecia comprises male's bald head and women's bald head.

Although some chemical compound of the present invention may present immunosuppressive activity, preferred compounds of the invention are nonimmunosuppressive as herein defined.

Preferably, in the method for the invention, these chemical compounds are formulated into pharmaceutical composition and are used for the treatment of or prevent various diseases as the aforementioned.Use the standard drug preparation technique, as Remington ' sPharmaceutical Sciences, Mack Publishing Company, Easton, those that PA. (1990) is disclosed.

Usually, for being administered systemically, the dosage that administration every day has the chemical compound of structure described herein is about 5 milligrams to about 3000 milligrams, preferred about 5 milligrams to about 1000 milligrams, more preferably from about 10 milligrams to about 100 milligrams.Should be understood that these dosage just as for example, can be adjusted the dosage of every day according to various factors.Whether with the concrete dosage of chemical compound to be administered and the persistent period and the treatment of treatment is partial or system, and these are complementary.Dosage and therapeutic scheme also depend on effect, the main body of this class factor such as used particular compound, treatment indication, chemical compound individual characteristics (as weight, age, sex and the medical conditions of main body), with the existence and the seriousness of any side effect of the compliance of therapeutic scheme and treatment.

According to the present invention, motif compound and pharmaceutically useful carrier (" carrier ") co-administered.Term used herein " pharmaceutically useful carrier " refers to one or more and is fit to deliver medicine to mammiferous compatible solid or liquid filler diluent or encapsulate material.Term used herein " compatible " refers to each component of compositions can be in one way and chemical compound blending of the present invention, blending each other, and described mode does not reduce the effect of compositions effect basically under common operating position.Certainly, carrier must have sufficiently high purity and enough low toxicity make it be fit to deliver medicine to the animal of being treated, preferably mammal.Carrier itself can be inert or it can have the pharmacy benefit of himself.

Compositions of the present invention can be suitable (for example) be used for oral, rectum, part, nose, eye or parenterai administration various forms of any one.In these forms, part or oral administration are particularly preferred.Depend on required specific administration approach, can use multiple pharmaceutically useful carrier well known in the art.These comprise solid or liquid filler, diluent, hydrotropic agent, surfactant and encapsulate material.Can comprise and not disturb the active optional pharmaceutically active substance of The compounds of this invention basically.The amount of uniting the carrier of use with chemical compound should be enough to provide the practical substances amount to administration per unit dosage chemical compound.The technology and the compositions of used preparation dosage form in the inventive method described: Modern Pharmaceutics, the 9th and 10 chapters, Banker in following reference paper; Rhodes edits (1979); People such as Lieberman, Pharmaceutical Dosage Forms:Tablets (1981) and Ansel, Introduction to Pharmaceutical Dosage Forms, second edition (1976).

Some examples that can be used as the material of pharmaceutically useful carrier or its component are that sugar is as lactose, dextrose plus saccharose; Starch such as corn starch and potato starch; Cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and methylcellulose; Atomizing Tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum; Kollag such as stearic acid and magnesium stearate; Calcium sulfate; Vegetable oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, Semen Maydis oil and cupu oil; Polyhydric alcohol such as propylene glycol, glycerol, sorbitol, mannitol and Polyethylene Glycol; Alginic acid; Emulsifying agent such as TWEENS; Wetting agent such as sodium lauryl sulfate; Coloring agent; Flavoring agent; Tablet agent, stabilizing agent; Antioxidant; Antiseptic; No pyrogene water; Isotonic saline solution and phosphate buffer.

To uniting the selection of pharmaceutically useful carrier of use basically by the decision of the route of administration of chemical compound with chemical compound of the present invention.

What particularly, be used to be administered systemically can comprise sugar, starch, cellulose and derivant thereof, Fructus Hordei Germinatus, gelatin, Talcum, calcium sulfate, vegetable oil, artificial oil, polyhydric alcohol, alginic acid, phosphate buffer, emulsifying agent, isotonic saline solution and not have pyrogene water by pharmaceutically useful carrier.The used preferred vector of parenterai administration comprises propylene glycol, ethyl oleate, ketopyrrolidine, ethanol and Oleum sesami.Preferably, the pharmaceutically useful carrier in the compositions of parenterai administration account for whole composition weight at least about 90%.

Multiple peroral dosage form be can use, this class solid form such as tablet, capsule, granule and loose powder comprised.These peroral dosage forms comprise the The compounds of this invention of safety, effective dose, are at least about 5%, preferred about 25% to about 50% usually.Tablet can be compacted, tabletting development, enteric coating coating, sweet tablet, film coating or multiple compacting, contains suitable binding agent, lubricant, diluent, disintegrating agent, coloring agent, correctives, guide of flow agent and fusing agent.Liquid oral dosage form comprises aqueous solution, Emulsion, suspension, by reconstituted solution of non-effervescive granule and/or suspension, by the reconstituted effervescent formulation of effervescent granule, it contains suitable solvent, antiseptic, emulsifying agent, suspending agent, diluent, sweetener, fusing agent, coloring agent and correctives.

The pharmaceutically useful carrier that is applicable to the unit dosage forms that preparation is oral is well known in the art.Tablet contains conventional compatible adjuvant such as the inert diluent of medicine usually, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; Binding agent such as starch, gelatin and sucrose; Disintegrating agent such as starch, alginic acid and croscarmelaose; Lubricant such as magnesium stearate, stearic acid and Talcum.Can use fluidizer (glidant) to improve the flow behavior of mixture of powders as silicon dioxide.Can add coloring agent such as FD ﹠amp; The C dyestuff improves outward appearance.Sweetener and flavoring agent such as aspartame, glucide, menthol, Herba Menthae and fruit flavoring agent are as the adjuvant of chewable tablets.Capsule (comprising releasing agent and slow releasing preparation in time) comprises above-mentioned disclosed one or more solid diluents usually.Auxiliary Consideration such as taste, cost and storage stability are depended in the selection of carrier component, and these factors are not important for purpose of the present invention and can be determined by those of ordinary skills.

Liquid preparations for oral administration also comprises liquid solution, Emulsion, suspension, powder, granule, elixir, tincture, syrup etc.The pharmaceutically useful carrier that is applicable to this based composition of preparation is well known in the art.The typical component that is used for the carrier of syrup, elixir, Emulsion and suspension comprises ethanol, glycerol, propylene glycol, Polyethylene Glycol, liquid sugar, Pyrusussuriensis alcohol and water.For suspension, typical suspending agent comprises methylcellulose, sodium carboxymethyl cellulose, AVICEL RC-591, yellow glue and sodium alginate; Typical wetting agent comprises lecithin and Spheron MD 30/70 (polysorbate 80); Typical preservatives comprises methyl butex and sodium benzoate.Fluid composition by oral (peroral) also can comprise one or more components, sweetener as indicated above, flavoring agent and coloring agent.

This based composition also can pass through the conventional method coating, usually the coating with pH or time dependence carries out, and makes like this to discharge or discharge to prolong required effect in the different time near the gastrointestinal tract of chemical compound of the present invention required local use location.This class dosage form generally includes but is not limited to one or more cellulose ethanoate phthalic acid esters, poly-acetic acid O-phthalic vinyl acetate (polyvinylacetate phthalate), hydroxypropylmethyl cellulose phthalate, ethyl cellulose, Eudragit coating, wax and lac.

Be used to realize that other compositions of systematicness transmission The compounds of this invention comprises Sublingual, cheek and nose dosage form.This based composition comprises one or more soluble packing materials such as sucrose, sorbitol and mannitol usually; Binding agent such as Acacia farnesiana Willd., microcrystalline Cellulose, carboxymethyl cellulose and hydroxypropyl emthylcellulose.Also can comprise above disclosed fluidizer, lubricant, sweetener, coloring agent, antioxidant and flavoring agent.

Chemical compound of the present invention also can come administration by local application.The carrier of topical composition preferably has and helps chemical compound of the present invention and infiltrate through in the skin with in the surrounding that arrives hair follicle.Topical composition of the present invention can be any form and comprise as solution, cream, ointment, gel, dew (lotion), shampoo, leave and rinsing type hair conditioner, milk, cleaning agent, wetting agent, spray, transdermal patches (skinpatches) etc.

Contain reactive compound topical composition can with variety carrier material well known in the art blend, described carrier mass such as water, alcohols, Aloe gel, allantoin, glycerol, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate etc.

Other material that is applicable to topical carrier comprises as emollient (emollient), solvent, wetting agent, thickening agent and powder.The example of each is as follows in the material of these types that can use separately or use as the mixture of one or more materials:

Emollient, as stearyl alcohol, single castor oil acid glyceride, glyceryl monostearate, propane-1, the 2-glycol, butane-1, the 3-glycol, ermine oil, spermol, the isostearic acid isopropyl ester, stearic acid, the Palmic acid isobutyl ester, Standamul 7061, oleyl alcohol, isopropyl laurate, lauric acid hexyl ester, decyl oleate, octadecane-2-alcohol, different spermol, cetin, dimethyl polysiloxane, n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, Polyethylene Glycol, 2,2'-ethylenedioxybis(ethanol)., lanoline, Oleum sesami, Oleum Cocois, Oleum Arachidis hypogaeae semen, Oleum Ricini, the lanonol of acetyl groupization, oil, mineral oil, butyl myristate, isostearic acid, Palmic acid, the linoleic acid isopropyl ester, Lauryl lactate, Tetradecyl lactate, decyl oleate and myristyl myristate; Propellant is as propane, butane, iso-butane, dimethyl ether, carbon dioxide and nitrous oxide; Solvent is as ethanol, dichloromethane, isopropyl alcohol, Oleum Ricini, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, oxolane; Wetting agent is as collagen, dibutyl phthalate and the gelatin of glycerol, sorbitol, 2-Pyrrolidone-5-carboxylic acid sodium, solubility; Powder is as the Magnesiumaluminumsilicate of Chalk, Talcum, bleaching earth, Kaolin, starch, natural gum (gum), silica sol, sodium polyacrylate, tetra-allkylammonium terre verte, trialkyl aryl terre verte, chemical modification, organically-modified illiteracy unsticking soil, aluminium silicate, pyrogenic silica, CVP Carbopol ETD2050, sodium carboxymethyl cellulose and the ethylene glycol monostearate of hydration.

Chemical compound of the present invention also can be with the form administration of liposome transfer system, as the form administration of small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be formed as cholesterol, stearylamine or phosphatidylcholine by various phospholipid.The local liposome of describing in used preferred formulation use of chemical compound of the present invention as the following file that transmits: people such as Dowton, " the liposome component transmits the influence of the cyclosporin A of encapsulate to the part: I. and use the mouse skin that does not have hair to carry out in vitro study ", S.T.PPharma Sciences, the 3rd volume, 404-407 page or leaf (1993), Wallach and Philippot, " novel lipid vesicle: Novasome  ", Liposome Technology, the 1st volume, 141-156 page or leaf (1993) and Wallach, US 4,911,928, transfer Micro-Pak, Inc., authorize March 27 nineteen ninety.

Chemical compound of the present invention also can pass through ionotherapy (iontophoresis) administration.Referring to, as, www.unipr.it/arpa/dipfarm/erasmus/erasm 14.html, people such as Banga, " be used for the iontophoretic treatment transporter that percutaneous transmits peptide/pharmaceutical grade protein " based on hydrogel, Pharm.Res., the 10th (5) volume, 697-702 page or leaf (1993), Ferry L.L., " be used for the iontophoretic theoretical model that transdermal drug transmits ", Pharmaceutical Acta Helvetiae, the 70th volume, 279-287 page or leaf (1995), people such as Gangarosa, " being used for the modern ionotherapy that topical remedy transmits ", Iht.J.Pharm, the 123rd volume, 159-171 (1995), people such as Green, " transmit a series of tripeptides " through the outer ionotherapy of skin volume, Pharm.Res., the 8th volume, 1121-1127 page or leaf (1991), people such as Jadoul, " fentanyl (Fentanyl) that transmits by the ionotherapy in the skin and TRH quantitatively and locate ", Int.J.Pharm., the 120th volume, 221-8 (1995), people such as O ' Brien, " its antiviral activity; the up-to-date summary of pharmacokinetics performance and therapeutic efficiency ", Drugs, the 37th volume, 233-309 page or leaf (1989), people such as Parry, " bioavaliability of acyclovir in the human body skin ", J.Invest.Dermatol., the 98th (6), 856-63 (1992), people such as Santi, " medicine of salmon calcitonin storage source composition and transmission in the percutaneous ionotherapy ", Pharrn.Res., the 14th (I) volume, 63-66 page or leaf (1997), people such as Santi, " the counter ion electric osmose therapy-mobile parameter of decision electric osmose: I.pH and ionic strength ", J.Control.Release, the 38th volume, 159-165 page or leaf (1996), people such as Santi, " the counter ion electric osmose therapy-mobile parameter of decision electric osmose: II. electrode chamber is formed ", J.Control.Release, the 42nd volume, 29-36 page or leaf (1996), people such as Rao, " non-infringement glucose monitoring in counter ion electric osmose therapy-human body ", Pharm.Res., the 12nd (12) volume, 1869-1873 page or leaf (1995), people such as Thysman, " in rat, transmit human calcitonin ", J.Pharm.Pharmacol., the 46th volume by ionotherapy, 725-730 page or leaf (1994), people such as Volpato, " strengthening the transmission of acyclovir ", Phann.Res. through nude mice skin by electricity repulsion and electric osmose ionotherapy, the the 12nd (11) volume, 1623-1627 page or leaf (1995).

Compositions of the present invention can also randomly comprise active reinforcing agent.Active reinforcing agent can be selected from multiple molecule, and these molecules can work by different way to strengthen the hair growth effect of chemical compound of the present invention.The active reinforcing agent of particular type comprises other hair growth stimulant and penetration enhancers.

Additional hair growth stimulant can be selected from multiple molecule, and these molecules can work by different way to strengthen the hair growth effect of chemical compound of the present invention.These other optional hair growth stimulant (if existence) amount ranges in compositions of the present invention usually are about 0.01-15% of composition weight, preferably about 0.1-10%, 0.5-5% most preferably from about.

Vasodilation such as potassium channel activator, comprise for example minoxidil (minoxidil) and minoxidil derivant such as aminexil and as following file in describe those: US 3,382,247, US 5,756, on May 26th, 092,1998 authorized, and US 5, on June 30th, 772,990,1998 authorized, US 5,760, and 043, on June 2nd, 1998 authorized, and US 5,328, on July 12nd, 914,1994 authorized, and US 5,466,694, authorize November 14 nineteen ninety-five, US 5,438,058, authorize and US 4 August 1 nineteen ninety-five, 973,474, authorize (all these patents are introduced the present invention as a reference) November 27 nineteen ninety, and cromakalin and diazoxide (diazoxide) can be used as the additional hair growth stimulant in the present composition.

Be applicable to that a kind of additional hair growth stimulant of the present invention is an androgen antagonist.The example of suitable androgen antagonist can be including but not limited to the 5-alpha-reductase inhibitors, carry the US 5 of (finasteride) and mandate on May 14th, 1996 as Fei Nasi, 516, people's such as 779 (introducing the present invention as a reference) and Nane, Cancer Research 58, those that describe in " C17; some novel inhibitors effect in vitro and in vivo of 20-lyase and 5 and its latent effect in the treatment carcinoma of prostate ", and cyproterone acetate, the US 5 that Azelaic Acid and derivant thereof and on January 2nd, 1996 authorize, 480, those chemical compounds of describing in 913, those materials of describing in flutamide (flutamide) and the following patent: US5,411,981, authorize May 2 nineteen ninety-five; US 5,565, and on October 15th, 467,1996 authorized; With US 4,910,226, authorize March 20 nineteen ninety, and all above-mentioned files are introduced the present invention as a reference.

Another kind of suitable optional hair growth stimulant is that immunosuppressant or non-immunosuppressant are as 1) cyclosporin and cyclosporin analog, comprise those that describe in the following files: the temporary transient patent application serial number 60/122 of the U.S., 925, people such as Fulmer, on March 5th, 1999 submitted to, introduce the present invention as a reference, with 2) the FK506 analog, those as describing in the following file: the temporary transient number of patent application 60/147,279 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,313 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,280 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,278 of the U.S., people such as Deeenhardt, on August 5th, 1999 submitted to; With the temporary transient number of patent application 60/147,276 of the U.S., people such as Eickhoff, on August 5th, 1999 submitted to; All these files are introduced the present invention as a reference.

Another kind of suitable optional hair growth stimulant is an antibacterial, as selenium sulfide, ketoconazole, triclocarban (triclocarbon), Triclosan (triclosan), 2-mercaptopyridine zinc oxide (zinc pyrithione), itraconazole, asiatic acid (asiatic acid), hinokitiol, mipirocin and EPA0,680, those that describe in 745 (introducing the present invention as a reference), clinacycin hydrochlorate, benzoyl peroxide, benzyl peroxide and minocycline (minocyclin).

The antibiotic medicine also can be used as optional hair growth stimulant and adds in the compositions of the present invention.The example of suitable antibiotic medicine can comprise glucocorticoid such as hydrocortisone, momestasone furoate and meticortelone, non-steroidal anti-inflammatory drug comprises cyclooxygenase or lipoxidase inhibitor, as U.S. Pat 5,756, those that describe in 092, and those chemical compounds of describing in benzydamine (benzydamine), salicylic acid and the following files: EPA 0,770,399 (on May 2nd, 1997 is open); WO94/06434 (on March 31st, 1994 is open) and FR 2,268,523 (on November 27th, 1975 is open) introduce the present invention as a reference with all these files.

Another kind of suitable optional hair growth stimulant is thyroxin and derivant and analog.The example that is applicable to thyroxin of the present invention comprises trilute.The example that is applicable to thyroid hormone analogs of the present invention comprises those that describe in the following files: the temporary transient number of patent application 60/136,996 of the U.S., people such as Zhang, on June 1st, 1999 submitted to, the temporary transient number of patent application 60/137,024 of the U.S., people such as Zhang, on June 1st, 1999 submitted to, the temporary transient number of patent application 60/137 of the U.S., 022, people such as Zhang, on June 1st, 1999 submitted to, the temporary transient number of patent application 60/137 of the U.S., 023, people such as Zhang, on June 1st, 1999 submitted to, the temporary transient number of patent application 60/137 of the U.S., 052, people such as Youngquist, on June 1st, 1999 submitted to, the temporary transient number of patent application 60/137 of the U.S., 063, people such as Youngquist, on June 1st, 1999 submitted to and the temporary transient number of patent application 60/136,958 of the U.S., people such as Youngquist, on June 1st, 1999 submitted to.

Prostaglandin agonists or antagonist also can be as the optional hair growth stimulant in the present composition.The suitable prostaglandin agonists or the example of antagonist comprise those that describe in latanoprost and the following files: WO98/33497, Johnstone, and on August 6th, 1998 is open; WO95/11003, Stjernschantz, April 27 nineteen ninety-five is open; JP 97-100091 (Ueno) and JP 96-134242 (Nakamura).

Being used for another kind of optional hair growth stimulant of the present invention is biostearin.Suitable biostearin comprises isotretinoin (isotretionoin), acitretin (acitretin) and tazarotene.

Being used for another kind of optional hair growth stimulant of the present invention is triterpenes, as describing in the following file those: people's such as Bradbury U.S. Patent application serial number 09/353,408, the method of hair growth " regulate " submitted and people such as Bradbury U.S. Patent application serial number 09/353 on July 15th, 1999,409, " contain the compositions that is useful on the triterpene of regulating hair growth ", on July 15th, 1999 submitted to, and it is introduced the present invention as a reference in full.

The optional hair growth stimulant that is used for other type of the present invention comprises class flavin (flavinoids), ascomycin derivative and analog, histamine antagonist example hydrochloric acid diphenhydramine, other triterpenes such as oleanolic acid (oleanolic acid) and ursolic acid (ursolic acid), as describing in the following file those: US 5,529,769, JP 10017431, WO95/35103, US 5,468,888, JP09067253, WO92/09262, JP 62093215, US 5,631,282, US 5,679,705, JP08193094, angle glycoside (saponins), as EP 0,558,509 (people such as Bonte), open and the WO97/01346 of JIUYUE in 1993 8 days people such as () Bonte, those that describe on January 16th, 1997 open (these two files are introduced the present invention as a reference), Dan Baijutang enzyme or glycosaminoglycans enzyme inhibitor such as US5,015,470, on May 14th, 1991 authorized, US 5,300, on April 5th, 284,1994 authorized and US 5,185,325, authorized (these patents are introduced the present invention as a reference) on February 9th, 1993, estrogen agonist and antagonist, pseudoterins, cytokine and somatomedin promoter, analog or inhibitor such as interleukin-1 inhibitor, interleukin-6 inhibitor, interleukin 10 promoter and tumor necrosis factor inhibitors, vitamin such as novel vitamin D analogues and pth antagonist, vitamin B12 analog and pantothenylol, interfuron agonist and antagonist, hydroxy acid such as US5,550, described in 158 those, benzophenone and hydantoin anticonvulsant such as phenytoin (phenytoin).

Other additional hair growth stimulant is described in detail in the following files: JP 09-157, and 139, people such as Tsuji, on June 17th, 1997 is open; EP 0277455 A1, Mirabeau, on August 10th, 1988 is open; WO97/05887, people such as Cabo Soler, on February 20th, 1997 is open; WO92/16186, people such as Bonte, on March 13rd, 1992 is open; JP 62-93215, people such as Okazaki, on April 28th, 1987 is open; US 4,987,150, people such as Kurono, and on January 22nd, 1991 authorized; JP 290811, people such as Ohba, and on October 1st 5,1992 is open; JP 05-286,835, people such as Tanaka, on November 2nd, 1993 is open; FR 2,723, and 31 3, Greff.1994 is open August 2; US 5,015,470, people such as Gibson, and on May 14th, 1991 authorized; US 5,559, and JIUYUE was authorized on the 24th in 092,1996 year; US 5,536, and on July 1st 6,751,1 996 authorized; US 5,714, and on February 3rd, 515,1998 authorized; EPA 0,319, and on June 14th, 991,1989 is open; EPA 0,357, and on October 6th, 630,1988 is open; EPA 0,573, and December disclosed on the 8th in 253,1993 years; JP 61-260010, on November 18th, 1986 is open; US 5,772, and on June 30th, 990,1998 authorized; US 5,053, and on October 1st, 410,1991 authorized; US 4,761, and on August 2nd, 401,1988 authorized; All above-mentioned files are introduced the present invention as a reference.

The non-limiting instance that can be used for the penetration enhancers of compositions of the present invention comprises as 2-methyl propan-2-ol, propan-2-ol, ethyl-2 hydroxy propanoic acid ester, oneself is-2 years old, the 5-glycol, POE (2) ether, two (2-hydroxypropyl) ether, penta-2, the 4-glycol, acetone, POE (2) methyl ether, 2 hydroxy propanoic acid, the 2-Hydroxycaprylic acid, third-1-alcohol, 1, the 4-diox, oxolane, fourth-1, the 4-glycol, propylene glycol dipelargonate, polyoxy propylidene 15 stearyl ethers, capryl alcohol, the POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, adipic acid two caprinoyl esters, diisopropyl adipate, Dermol DIPS, dibutyl sebacate, ethyl sebacate, dimethyl sebacate, di-n-octyl sebacate, the suberic acid dibutyl ester, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, di-n-butyl succinate, didecyl phthalate, decyl oleate, ethyl hexanoate, ethyl salicylate, isopropyl palmitate, ethyl laurate, n-nonanoic acid 2-ethyl-hexyl ester, the isostearic acid isopropyl ester, butyl laurate, benzyl benzoate, butyl benzoate, lauric acid hexyl ester, ethyl caprate, ethyl caprilate, butyl stearate, benzyl salicylate, 2 hydroxy propanoic acid, the 2-Hydroxycaprylic acid, dimethyl sulfoxide, N, the N-dimethyl acetylamide, N, dinethylformamide, 2-Pyrrolidone, 1-Methyl-2-Pyrrolidone, the 5-N-methyl-2-2-pyrrolidone N-, 1,5-dimethyl-2-Pyrrolidone, the 1-ethyl-2-pyrrolidone, phosphine oxide, sugar ester, tetrahydrofurfuryl alcohol, urea, diethyl--toluamide and 1-dodecyl-aza-cycloheptane-2-ketone.

Certainly, at all above, being used for the chemical compound of the inventive method can be individually dosed or with the form administration of mixture, and compositions of the present invention can also comprise additional medicine or the excipient that is applicable to indication.

The embodiment of compositions administration

The following example is not restriction the present invention, but provides indication to those of ordinary skill, implements method of the present invention.In each embodiment, the The compounds of this invention except being mentioned can be substituted in an embodiment, and has similar result.

Embodiment A

Preparation is used for topical drug delivery composition, comprises:

Component	Consumption
		The chemical compound of embodiment 2	5％
Ethanol	57％
		Propylene glycol	19％
Different sorbic acid dimethyl ester (dimethyl isosorbide)	19％

Male's bald head patient treats with method of the present invention.Concrete scheme is the local above-claimed cpd that uses every day, continues for 6 weeks.

Embodiment B

According to people such as Dowton " liposome composition transmits the influence of the cyclosporin A of encapsulate to the part: I. use atrichous mouse skin to carry out in vitro study ", S.T.P Pharma Sciences, the 3rd volume, 404-407 page or leaf (1993) uses the chemical compound of embodiment 1 to replace cyclosporin A and use Novasome 1 to form as the nonionic liposome preparing the topical drug delivery composition according to the present invention.

The male patient who suffers from the alopecia of male's mode with above-mentioned composition treatment every day.Concrete scheme is to give 6 weeks of patient's topical above-mentioned composition.

Embodiment C

The preparation shampoo comprises:

Component	Embodiment C-1	Embodiment C-2	Embodiment C-3	Embodiment C-4
					Ammonium lauryl sulfate	????11.5％	????11.5％	????9.5％	????7.5％
Lauryl polyethenoxy ether sodium sulfate	????4％	????3％	????2％	????2％
					Coconut monoethanol amide	????2％	????2％	????2％	????2％
Glycol distearate	????2％	????2％	????2％	????2％
					Spermol	????2％	????2％	????2％	????2％

Stearyl alcohol	????1.2％	????1.2％	????1.2％	????1.2％
					Glycerol	????1％	????1％	????1％	????1％
Polyquatemium?10	????0.5％	????0.25％	????-	????-
					Polyquatemium?24	????-	????-	????0.5％	????0.25％
Sodium chloride	????0.1％	????0.1％	????0.1％	????0.1％
					The Olestra of Cotton Gossypii acid fatty acid	????3％	????3％	????-	????-
The Olestra of behenic acid fatty acid	????2％	????3％	????-	????-
					Polydimethylsiloxane	????-	????-	????3％	????2％
Cocos nucifera oil aminopropyl betanin	????-	????1％	????3％	????3％
					Lauryl dimethyl amine oxide	????1.5％	????1.5％	????1.5％	????1.5％
The decyl polydextrose	????-	????-	????1％	????1％
					DMDM Hydantoin	????0.15％	????0.15％	????0.15％	????0.15％
The chemical compound of embodiment 3	????-	????-	????3％	????-
					The chemical compound of embodiment 4	????-	????-	????-	????6％
Phenyl phenol	????0.5％	????0.5％	????0.5％	????0.5％
					Spice	????0.5％	????0.5％	????0.5％	????0.5％
Water	In right amount	In right amount	In right amount	In right amount

Male's bald head patient treats with method of the present invention.Concrete scheme is the local above-claimed cpd that uses every day, continues for 12 weeks.

Claims (8)

1. treat the method for alopecia, comprise that described compositions comprises to a kind of compositions of clothes:

(a) have the non-immunosuppressive compounds of following array structure:

But and the amide of pharmaceutically useful salt, hydrate and biological hydrolysis, ester and inferior amide, wherein:

(ⅰ) Q is first hetero atom, and wherein first hetero atom is a nitrogen;

(ⅱ) G is selected from C ₁-C ₆Alkyl, C ₁-C ₆Alkenyl, C ₅-C ₇Cycloalkyl, C ₁-C ₄The C that alkyl replaces ₅-C ₇Cycloalkenyl, C ₂-C ₄The C that alkenyl replaces ₅-C ₇Ar and Ar that the Ar that cycloalkenyl, alkyl replace, alkenyl replace;

(ⅲ) Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, piperazinyl, piperidyl, monocyclic heterocycles, bicyclic heterocycle, and wherein Ar randomly is selected from following substituent group independently of one another and replaces by one or more: hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₁-C ₄Alkoxyl, benzyloxy, phenoxy group, 1,2-methylene-dioxy, amino, carboxyl and phenyl;

(ⅳ) J is selected from hydrogen, C ₁-C ₂Alkyl and benzyl; K is selected from C ₁-C ₄Alkyl, benzyl and cyclohexyl methyl; Or J and K can be joined together to form 5-, 6-or 7-unit heterocycle, and wherein this ring can randomly comprise and is selected from O, S, S (O), S (O) ₂Other hetero atom;

(ⅴ) A is selected from CH ₂, O and NR ₁, R wherein ₁Be selected from hydrogen and C ₁-C ₄Alkyl;

(ⅵ) B and D are selected from hydrogen, Ar, C independently of one another ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Alkyl, C ₅-C ₇The C of cycloalkyl substituted ₂-C ₆Alkenyl, C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₂-C ₆Alkenyl, C ₁-C ₆Ar, C that alkyl replaces ₁-C ₆Ar, C that alkenyl replaces ₁-C ₆Assorted alkyl, C ₂-C ₆Heterochain thiazolinyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Assorted alkyl, C ₅-C ₇The C of cycloalkyl substituted ₂-C ₆Heterochain thiazolinyl, C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Assorted alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₂-C ₆Heterochain thiazolinyl, C ₁-C ₆Ar, C that assorted alkyl replaces ₂-C ₆The Ar of heterochain alkenyl substituted, and

Wherein Z is selected from hydrogen, C ₁-C ₆Alkyl and C ₂-C ₆Alkenyl, and wherein T is selected from Ar and 5-, 6-or 7-unit cycloalkyl, and it is selected from hydrogen, hydroxyl, C ₁-C ₄At least one substituent group of alkoxyl and oxo replaces; Wherein at least one among B and the D is not hydrogen; And

(ⅶ) m is 0 to 3 integer; And

(b) pharmaceutically useful carrier.

2. the process of claim 1 wherein that J and K are joined together to form 5-, 6-or 7-unit ring.

3. the method for aforementioned each claim, wherein J and K are joined together to form 5-unit ring.

4. claim 1 or 2 method, wherein J and K are joined together to form 6-unit ring.

5. the method for aforementioned each claim, wherein A is-O-.

6. each method among the claim 1-4, wherein A is-NH-.

7. the method for aforementioned each claim, wherein administration is that carry out the part.

8. the method for aforementioned each claim, wherein administration is oral.