CN1332722A - 2-substituted Retoamides - Google Patents

Abstract

The present disclosure describes novel compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression.

Description

The keto-amide that 2-replaces

Invention field

The present invention relates to be specially adapted to treat the new compound and the composition of Mammals alopecia, the alopecia of described treatment Mammals comprises prevention and/or reverse hair loss and promotes hair growth.Compound of the present invention and composition also can be used for resisting multiple disease, comprise for example anti-multiple medicines, HIV (human immunodeficiency virus) (HIV), heart and injury and nervous disorders, and can be used for controlling parasite and cause immunosuppression.

Cross-index

According to the 35th of United States Code the 119th (e), the provisional application serial number 60/102,448 that the application submitted to on September 30th, 1998 is a right of priority.

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 process usually because of using some.This class alopecia is attended by the long shortage of hair regeneration usually, thereby causes the bald or whole alopecia of part.This class baldness considers to lack magnetism 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 cycle of activity that comprises growth and rest alternate periods.This cycle is divided into the anagen of being known as usually, three main phase of catagen and telogen.The anagen be the vegetative period 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 transitory 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 baldness.

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 application minoxidil (minoxidil) is (by Pharmacia ﹠amp; Upjohn sells with Rogaine ) and oral Fei Nasi carry (finasteride) (by Merck﹠amp; 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 study 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 severe side effect, comprises vasorelaxation (it causes fluid to remain on around the heart and increases heart rate), expiratory 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 impotence, sexual desire reduction, ejaculate volume reduction, breast tenderness and increase and allergy, comprises lip swelling and skin rash.And women and children 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 of Medicine, the 338th volume, the 9th phase, on February 26th, 1998.

What is interesting is that known immunosuppressor cyclosporin A and FK506 can cause significant crinosity 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 Wyeth-Ayerst Laboratories (Rapamycin) influence initial to hair growth in the mouse: the growth of new hair does not need immunosuppression ", Journal ofDermatological Science, the 9th volume, 64-69 page or leaf (1995); People such as Yamamoto, " cyclosporin A and FK506, effective immunosuppressor, 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 topical application FK506, effective immunosuppressor, stimulating hair growth ", Journal ofInvestigational Dermatology, the 102nd volume, 160-164 page or leaf (1994); People such as Jiang, " by topical application FK506, effective immunosuppressor is the anagen of inducing in the mouse skin of telogen ", Journal of Investigational Dermatology, the 104th volume, 523-525 page or leaf (1995); People such as McElwee, " local FK506: be used for the effective immunotherapy of alopecia bunch (Alopecia Areata)? use Dundee to test the research of bald mouse model ", Britisn Journal ofDermatology, the 137th volume, 491-497 page or leaf (1997); People such as Maurer, " regulating hair growth ", American Journal of Pathology, the 150th volume, the 4th phase, 1433-1441 (1997) by local immunophilin part; With people such as Paus, " by immunosuppression control hair growth ", Arch.Dermatol.Res, the 288th volume, 408-410 page or leaf (1996).But, because these compounds as the remarkable effectiveness of immunosuppressor, 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, 1457-1460 page or leaf (1994).Disclose and had the very similar analogue that should the big ring of complexity that the hair growth performance is for example alopecia bunch and/or male baldness form.Referring to, as people such as Kawai, USP5,541,193, transfer Abbott Laboratories, on July 30th, 1996 authorized; People such as Asakura, USP5,496,564, transfer Fujisawa Pharmaceutical Co., on March 5th, 1996 authorized; People such as Baumann, USP5,352,671, transfer Sandoz Ltd., on October 4th, 1994 authorized; And people such as Rupprecht, USP5,550,233, transfer Merck﹠amp; Co., Inc., on August 27th, 1996 authorized.

But, relate to the active excitement of crinosity of cyclosporin A and FK506, to a certain extent, calmed down not as the shortage of the report of the immunosuppression of littler, the non-big ring FK506 complexity, various and non-immunosuppressive compounds hirsutism by relevant structure.Referring to, people such as Steiner, WO 96/40140, transfers Guilford Pharmaceuticals, Inc., on December 19th, 1996 is open; People such as Hamilton, WO 96/40633, transfers Guilford Pharmaceuticals, Inc., on December 19th, 1996 is open; People such as Steiner, USP5,696,135, transfer GPI NIL Holdings, Inc., on December 9th, 1997 authorized; People such as Hamilton, US5,614,547, 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, WO 96/36630, transfers Vertex Pharmaceuticals, Inc., on November 21st, 1996 is open; People such as Armistead, WO 97/36869, transfers Vertex Pharmaceuticals, Inc., on October 9th, 1997 is open; People such as Zelle, WO 96/15101, transfers Vertex Pharmaceuticals, Inc., on May 23rd, 1996 is open; People such as Armistead, WO 92/19593, transfers Vertex Pharmaceuticals, Inc., on November 12nd, 1992 is open; People such as Armistead, WO 94/07858, transfers VertexPharmaceuticals, Inc., on April 14th, 1994 is open; People such as Zelle, WO 95/26337, transfers Vertex Pharmaceuticals, Inc., October 5 nineteen ninety-five is open; People such as Duffy, WO92/21313 transfers Vertex Pharmaceuticals, Inc., on December 10th, 1992 is open; People such as Armistead, USP5,192,773, transfer Vertex Pharmaceuticals, Inc., on March 9th, 1993 is open; People such as Armistead, USP5,330,993, transfer Vertex Pharmaceuticals, Inc., on July 19th, 1994 authorized; People such as Armistead, USP5,622,970, transfer VertexPharmaceuticals, Inc., on April 22nd, 1997 authorized; People such as Armistead, USP5,654,332, transfer Vertex Pharmaceuticals, Inc., on August 5th, 1997 authorized; People such as Armistead, USP5,620,971, transfer Vertex Pharmaceuticals, Inc., on April 15th, 1997 authorized; People such as Zelle, USP5,543,423, transfer Vertex Pharmaceuticals, Inc., on August 6th, 1996 authorized; People such as Armistead, USP5,516,797, transfer Vertex Pharmaceuticals, Inc., on May 14th, 1996 authorized; People such as Armistead, USP5,665,774, transfer VertexPharmaceuticals, Inc., on September 9th, 1997 authorized; People such as Andres, " analogue 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 immunosuppressor FK506 ", ActaCrystallographica, D51,522-528 page or leaf (1995).

Surprisingly, the present inventor has had been found that a new compounds, its prevention and/or reverse hair loss or promote hair growth, but do not have complexity, the macrocyclic structure of FK506.But the present inventor has further found to cause hair growth is wonderful non-immunosuppressant or have a compound of small inhibitive ability of immunity in the compound of this new classification.Compare the reduction of the immunosuppressive activity of these crinosity compounds and/or to lack be tangible benefit with FK506 with the immunosuppressive compounds cyclosporin A.

Summary of the invention

The present invention relates to be specially adapted to treat the new compound and the composition of Mammals alopecia, the alopecia of described treatment Mammals comprises prevention and/or reverse hair loss and promotes hair growth.Compound of the present invention and composition also can be used for resisting multiple disease (disorder), comprise for example anti-multiple medicines, HIV (human immunodeficiency virus) (HIV), heart and injury and nervous disorders, and can be used for controlling parasite and cause immunosuppression.Compound of the present invention has following array structure:

But and the acid amides of pharmaceutically useful salt, hydrate and biological hydrolysis, ester and inferior acid amides, wherein substituting group Z, W, X, Y, V, A, G, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₉And R ₁₀As defined herein.

Detailed Description Of The Invention

The present invention relates to be specially adapted to treat the new compound and the composition of Mammals alopecia, the alopecia of described treatment Mammals comprises prevention and/or reverse hair loss and promotes hair growth.

Except finding that compound of the present invention is suitable for treating the alopecia, the present inventor is surprisingly found out that also the hair growth stimulation does not need immunosuppression.The present inventor has further found to be used for the treatment of alopecia but has been the compound of non-inhibitive ability of immunity astoundingly.Therefore, preferred compound of the present invention, such as herein defined, be non-inhibitive ability of immunity.Compound of the present invention also is applicable to treatment multiple other disease hereinafter described.

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 percentage ratios used herein, ratio and ratio 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 forms on any acidity (as carboxyl) group, or the anion salt that forms on any alkalescence (as, amino) group.Many in this class salt are well known in the art.Preferred cation salt comprise an alkali metal salt (as, sodium salt and sylvite), alkaline earth salt (as magnesium salts and calcium salt) and organic salt.Preferred anionic surfactants salt comprises halogenide (as villaumite).When administration, the acceptable salt of this class must be suitable for Mammals to be used.

Unless specialize, term used herein " alkenyl " be unsubstituted or that replace, straight or branched, have 2 to about 15 carbon atoms, preferred 2 to about 10 carbon atoms, more preferably 2 to about 8 carbon atoms and 2 hydrocarbon chain groups most preferably from about to about 6 carbon atoms.Alkenyl has at least one olefinic double bond.The non-limiting instance of alkenyl comprises vinyl, allyl group and butenyl.

Unless specialize, 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.The-oxyl residue can be replacement or unsubstituted.

Unless specialize, term used herein " aryloxy " is the oxygen residue with aryl substituent.The aryloxy residue can be replacement or unsubstituted.

Unless specialize, term used herein " alkyl " be unsubstituted or that replace, straight or branched, have 1 to about 15 carbon atoms, preferred 1 to about 10 carbon atoms, more preferably 1 to about 6 carbon atoms and 1 saturated hydrocarbon chain group most preferably from about to about 4 carbon atoms.Preferred alkyl comprises for example methyl, ethyl, propyl group, sec.-propyl and butyl.

Term used herein " alkylene (alkylene) " refers to alkyl, alkenyl or alkynyl for two residues.For example, " methylene radical " is-CH ₂-.Alkylene can be replacement or unsubstituted.

Unless specialize, term used herein " aryl " is to be carbocyclic ring or heterocyclic aromatic ring residue.Preferred aryl groups comprises for example phenyl, benzyl, tolyl, xylyl, cumyl, naphthyl, xenyl, thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl, triazolyl, tetrazyl, benzothiazolyl, benzofuryl, indyl, indenyl, the camomile cyclic group, fluorenyl, anthryl oxazolyl isoxazolyl, different triazolyl, imidazolyl, pyrazolyl (pyraxoly) oxadiazole base, the indolizine base, indyl, pseudoindoyl, purine radicals, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl etc.Aryl can be that replace or unsubstituted.

Unless specialize, term used herein " aromatic yl alkenyl " is with the alkenyl of aryl replacement or the aryl that replaces with alkenyl.Aromatic yl alkenyl can be that replace or unsubstituted.

Unless specialize, term used herein " arylalkyl " is with the alkyl of aryl replacement or the aryl that replaces with alkyl.The preferred aryl groups alkyl comprises benzyl, styroyl and hydrocinnamyl.Arylalkyl can be that replace or unsubstituted.

Term used herein " but acid amides of biological hydrolysis " is the active of not interfering compound or the acid amides that is changed into the compound of the present invention of active compound easily in the Mammals main body body.

Term used herein " but ester of biological hydrolysis " is the active of not interfering compound or the ester that is changed into the compound of the present invention of active compound easily in the Mammals main body body.

Term used herein " but inferior acid amides of biological hydrolysis " is the active of not interfering compound or the inferior acid amides that is changed into the compound of the present invention of active compound easily in the Mammals main body body.

Unless specialize, term used herein " carbocyclic ring " or similar terms are hydrocarbon ring residues.Carbocyclic ring is that monocycle or fused rings, bridging ring or volution encircle more.Unless specialize, monocycle contain 3 to about 9 atoms, preferred about 4 to about 7 atoms, 5 or 6 atoms most preferably.Many rings contain have an appointment 7 to about 17 atoms, preferred about 7 to about 14 atoms, 9 or 10 atoms most preferably from about.Carbocyclic ring can be that replace or unsubstituted.

Unless specialize, term used herein " cycloalkyl " is saturated carbocyclic ring or heterocycle residue.Preferred cycloalkyl comprises for example cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl can be that replace or unsubstituted.

Unless specialize, " halo ", " halogen ", " halogenide " etc. refer to chlorine, bromine, fluorine or iodine atom residue, and preferably bromine, chlorine or fluorine are more preferably chlorine or fluorine.

Unless specialize, term used herein " heterochain thiazolinyl " is to contain carbon atom and one or more heteroatomic alkenyl residue (as ,-CHOCH at the alkenyl chain ₂, rather than heteroatoms exists as side chain, and as C (O)), wherein heteroatoms is selected from oxygen, sulphur, nitrogen and phosphorus, is more preferably oxygen, sulphur and nitrogen.The heterochain thiazolinyl can be that replace or unsubstituted.

Unless specialize, term used herein " assorted alkyl " is to contain carbon atom and one or more heteroatomic alkyl residue (as ,-CH at alkyl chain ₂OCH ₂, rather than heteroatoms exists as side chain, and as C (O)), wherein heteroatoms is selected from oxygen, sulphur, nitrogen and phosphorus, is more preferably oxygen, sulphur and nitrogen.Assorted alkyl can be that replace or unsubstituted.

Unless specialize, term used herein " heteroaryl " be aryl rings contain carbon atom and one or more heteroatomic aromatic yl residue (as,-CHOCH, rather than heteroatoms exists as side chain, as C (O)), wherein heteroatoms is selected from oxygen, sulphur, nitrogen and phosphorus, is more preferably oxygen, sulphur and nitrogen.Heteroaryl can be that replace or unsubstituted.

Unless specialize, term used herein " heteroaryl alkenyl " is the aromatic yl alkenyl residue, and wherein aryl is that heteroaryl and/or alkenyl are the heterochain thiazolinyls.The heteroaryl alkenyl can be that replace or unsubstituted.

Unless specialize, term used herein " heteroarylalkyl " is the arylalkyl residue, and wherein aryl is that heteroaryl and/or alkyl are assorted alkyl.Heteroarylalkyl can be that replace or unsubstituted.

Unless specialize, term used herein " heterocycle " or similar terms are the ring residues that is made of intra-annular carbon atom and one or more heteroatoms, and wherein heteroatoms is selected from oxygen, sulphur, nitrogen and phosphorus, is more preferably oxygen, sulphur and nitrogen.Heterocycle is that monocycle or fused rings, bridged ring or volution encircle more.Unless specialize, monocycle contain 3 to about 9 atoms, preferred about 4 to about 7 atoms, 5 or 6 atoms most preferably.Many rings 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.

Unless specialize, term used herein " Heterocyclylalkyl " is saturated heterocycle.Heterocyclylalkyl can be that replace or unsubstituted.

Unless specialize, 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 Mammals.

Term used herein " compound of safe and effective amount " (or composition etc.) refers to present bioactive significant quantity, preferred wherein biological activity is reactive site prevention and/or the reverse hair loss in the Mammals 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.

Term used herein " volution part " is a loop section of sharing a carbon with another ring, preferred Z ring.This class volution part can be carbocyclic ring or heterocycle.The volution part can be that replace or unsubstituted.

Unless specialize, this paper used term " replacement " when relating to group, part etc. refers to have one or more substituting groups, each substituting group be independently selected from hydrogen,-oxyl, hydroxyl, nitro, amino, alkylamino, cyano group, halo, carboxyl, thiol, imino-and aryloxy (substituting group that also allows in addition on the G part be selected from oxo, amido ,-O-alkyl-C (O) OR ₃₂With-O-alkyl-C (O) NHR ₃₂, R wherein ₃₂Be selected from hydrogen and alkyl), preferably hydrogen,-oxyl, aryloxy, hydroxyl, nitro, amino, halo and thiol, be more preferably hydrogen,-oxyl, hydroxyl, nitro, amino, alkylamino and halo, further preferably hydrogen, halo, hydroxyl and-oxyl most preferably are hydrogen.

Unless specialize, term used herein " unsubstituted " refers to be replaced by hydrogen.But also can as one man being described as group wherein, substituting group be " replacement " of hydrogen.

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.

Compound of the present invention

Compound of the present invention has following array structure:

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

(a) Z is saturated or undersaturated 4-, 5-, 6-, 7-, 8-or 9-person's carbocyclic ring or a heterocycle, and wherein heterocycle contains one or more O of being selected from, N, S, S (O), S (O) ₂And the heteroatoms of P ((O) OK);

(b) V is-CU-, and wherein U is selected from hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(c) G be selected from zero, O, S and NR ₁₇

(d) K is selected from hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(e) R ₁Be selected from alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(f) W be selected from zero, hydrogen and low alkyl group;

(g) A is selected from the zero-sum alkyl;

(h) X and Y are selected from C (O), P (O), N, O and S independently of one another, wherein:

(i) when X is C (O), R so ₃Be zero and Y be selected from N, O and S;

(ii) when X is P (O), R so ₃Be zero and Y be selected from N and O;

(iii) when X is N, R so ₃Be selected from hydrogen, alkyl and aralkyl, Y is selected from C (O) and P (O) and R ₂Be zero;

(iv) when X is O, R so ₃Be zero, Y is selected from C (O) and P (O) and R ₂Be zero;

(v) when X is S, R so ₃Be zero, Y is C (O) and R ₂Be zero;

(i) R ₂And R ₃Be selected from zero independently of one another, hydrogen, alkyl and aralkyl;

(j) R ₄It is alkyl;

(k) R ₅And R ₆Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl with at least two carbon atoms; Or R wherein ₅And R ₆Be joined together to form carbocyclic ring or heterocycle;

(1) R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, halogen, cyano group, hydroxyl, oxo, imino-,-R ₁₄SR ₁₅,-R ₁₄S (O ₂) R ₁₅,-R ₁₄S (O) R ₁₅,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄C (O) OR ₁₅,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆,-R ₁₄P (O) NR ₁₅R ₁₆,-R ₁₄P (O) OR ₁₅R ₁₆With the volution part, and R wherein ₇And R ₈Can randomly be joined together to form aromatics or saturated, carbocyclic ring or heterocycle, wherein this ring is fused on the Z;

(m) R ₁₄And R ₁₅Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl; With

(n) R ₁₆And R ₁₇Be selected from hydrogen and alkyl independently of one another.

Member ring systems Z

Compound of the present invention is made of member ring systems Z, and it is saturated or unsaturated 4-, 5-, 6-, 7-, 8-or 9-person's carbocyclic ring or heterocycle.Preferred Z member ring systems is 5-, 6-or 7-person's carbocyclic ring or heterocycle, is more preferably 5-or 6-person's carbocyclic ring or heterocycle.Preferred Z ring is a carbocyclic ring.

The V substituting group is in the 1-position of member ring systems, this substituting group is-CU-, wherein U is selected from hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl, preferably hydrogen, alkyl and aralkyl most preferably are hydrogen.

The Z ring is optional to be contained one or more heteroatomss or contains heteroatom moiety (for the sake of simplicity, this paper is described as heteroatoms with them), and wherein heteroatoms is selected from oxygen (O), nitrogen (N), sulphur (S), sulfoxide S (O), sulfone S (O) ₂And phosphonate (P ((O) OK)).Preferred optional heteroatoms is selected from O, N, S, S (O) and S (O) ₂Certainly, owing to need the V substituting group at 1, so heteroatoms can not be at 1.

When N was heteroatoms in the heterocycle, other N heteroatoms must replace, and most preferably replaces with hydrogen or alkyl.For the sake of clarity, following table 1 will be described S (O), S (O) ₂And P ((O) OK) heteroatoms:

Table 1

The G part

G partly is directly connected on the V substituting group.G is selected from zero, O, S and NR ₁₇, R wherein ₁₇Be selected from hydrogen and alkyl.Preferred G is selected from O, S and NR ₁₇, preferably O and NR ₁₇, most preferably G is NR ₁₇

R ₁Part

As pre-structure was shown, keto-amide partly was directly connected on the G part.R ₁Side chain also is directly connected on the keto-amide part.R ₁Part is selected from alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl.R ₁Part is preferably replaced by the substituting group that at least one is different from hydrogen.Except the substituting group that can on all parts, replace defined herein, substituting group oxo, amido ,-O-alkyl-C (O) OR ₃₂With-O-alkyl-C (O) NHR ₃₂(R wherein ₃₂Be selected from hydrogen and alkyl) also can be at R ₁Replace on the part.

R ₁Part is preferably selected from alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl and heteroaralkyl, more preferably is selected from aryl, aralkyl and heteroaralkyl, most preferably is aryl.R ₁The used most preferred aryl of part is replaced by aryl (most preferably being the phenyl that replaces), particularly has the substituent aryl of at least one-oxyl.In the following table 2 particularly preferred R has been shown ₁Part.The preferred R of table 2- ₁Part

The A-X-Y-R that replaces ₄Part

A-X-Y-R ₄Part is at 2 of the Z ring, and as described herein, this part is by R ₂, R ₃, R ₅And R ₆Replace.

The A of side chain partly is selected from the zero-sum alkyl.The A part most preferably is zero.Certainly, when A was zero, X was directly connected on the Z ring.

The X of side chain depends in part on the structure of Y part, and vice versa.X and Y are selected from C (O) (that is, carbonyl), P (O), N, O, S independently of one another, and have following restricted condition:

(i) when X is C (O), R so ₃Be zero and Y be selected from N, O and S;

(ii) when X is P (O), R so ₃Be zero and Y be selected from N and O;

(iii) when X is N, R so ₃Be selected from hydrogen, alkyl and aralkyl, Y is selected from C (O) and P (O) and R ₂Be zero;

(iv) when X is O, R so ₃Be zero, Y is selected from C (O) and P (O) and R ₂Be zero;

(v) when X is S, R so ₃Be zero, Y is C (O) and R ₂Be zero;

Preferably, X and Y are selected from C (O), N and O independently of one another.More preferably, X and Y are selected from C (O) and N independently of one another.

X and Y are respectively by R ₃And R ₂Replace.R ₃And R ₂Be selected from zero independently of one another, hydrogen, alkyl and aralkyl.When X is N, R so ₃Be selected from hydrogen, alkyl and aralkyl, preferably hydrogen and alkyl most preferably are hydrogen.When Y is N, R so ₂Being selected from hydrogen, alkyl and aralkyl, being more preferably hydrogen and alkyl, most preferably is hydrogen.

R ₄Part is a moieties.Preferred moieties has preferred restricted condition mentioned above, and most preferred R ₄Part is that methylene radical or methyne (that is, only have a substituent C of hydrogen ₁Part).

R ₅And R ₆Part is directly connected to R separately ₄On.R ₅And R ₆Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl with at least two carbon atoms; Perhaps R wherein ₅And R ₆Be joined together to form carbocyclic ring or heterocycle; R wherein ₅And R ₆In at least one is not zero or hydrogen.

Preferably, R ₅And R ₆Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl with at least two carbon atoms.More preferably, R ₅And R ₆Be selected from the alkyl with at least two carbon atoms, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl and heteroaralkyl independently of one another.Most preferably, R ₅And R ₆Be aralkyl independently of one another.Usually preferred R ₅And R ₆It is suitable part.Certainly, R ₅And R ₆Can be substituted independently of one another.The R of illustrative has been shown in the following table 3 ₅And R ₆Part.

The R of table 3-illustrative ₅And R ₆Part

The W part

The Z ring can be replaced by another part W at 2.W partly is selected from zero, hydrogen and low alkyl group, and preferably hydrogen and low alkyl group most preferably are hydrogen.When W was low alkyl group, W most preferably was a methyl.

Z ring substituents R ₇, R ₈, R ₉And R ₁₀

Except 1 of above-mentioned Z ring and 2 s' substituting group, also can have other substituting group on other position that Z encircles, the other substituting group of this class is defined as R ₇, R ₈, R ₉And R ₁₀These substituent R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, halo, cyano group, hydroxyl, oxo, imino-,-R ₁₄SR ₁₅,-R ₁₄S (O ₂) R ₁₅,-R ₁₄S (O) R ₁₅,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄C (O) OR ₁₅,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆,-R ₁₄P (O) NR ₁₅R ₁₆,-R ₁₄P (O) OR ₁₅R ₁₆With volution part, wherein R ₇And R ₈Can choose wantonly and be joined together to form aromatics or saturated, carbocyclic ring or heterocycle, wherein ring is fused on the Z.R ₁₄And R ₁₅Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl.R ₁₆Be selected from hydrogen and alkyl.

Preferably, R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, halo, cyano group, hydroxyl, oxo ,-R ₁₄SR ₁₅,-R ₁₄S (O) ₂R ₁₅,-R ₁₄S (O) R ₁₅,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆With volution part, wherein R ₇And R ₈Can choose wantonly and be joined together to form aromatics or saturated, carbocyclic ring or heterocyclic second ring, wherein this second ring is fused on the Z.More preferably, R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, assorted alkyl, heterochain thiazolinyl, aryl, aralkyl, heteroaralkyl, halo, hydroxyl, oxo ,-R ₁₄SR ₁₅,-R ₁₄S (O) ₂R ₁₅,-R ₁₄S (O) R ₁₅,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆With volution part, wherein R ₇And R ₈Can choose wantonly and be joined together to form aromatics or saturated, carbocyclic ring or heterocyclic second ring, wherein this second ring is fused on the Z.Further preferably, R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, assorted alkyl, heterochain thiazolinyl, aryl, aralkyl, heteroaralkyl, halo, hydroxyl, oxo ,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆With volution part, wherein R ₇And R ₈Can choose wantonly and be joined together to form aromatics or saturated, carbocyclic ring or heterocyclic second ring, wherein this second ring is fused on the Z.Most preferably, R ₇And R ₈Can choose second ring that is joined together to form aromatics or saturated (preferably aromatics), carbocyclic ring or heterocycle (preferably carbocyclic ring) wantonly, wherein this second ring is fused on the Z.

Work as R ₇And R ₈Be joined together to form aromatics or saturated, carbocyclic ring or heterocyclic second ring, when wherein this second ring was fused to Z and goes up, second ring certainly was that replace or unsubstituted.Preferred second ring is a phenyl ring.

The compound of illustrative of the present invention shown in the following table.

The compound of table 4-illustrative of the present invention

The compound of table 5-illustrative of the present invention

Wherein, in table 5, R ₁₈, R ₁₉And R ₂₀Be selected from hydrogen,-oxyl, aryloxy, hydroxyl, nitro, amino, halo and thiol independently of one another.

The compound of table 6-illustrative of the present invention Wherein, in table 6, R ₃₀Be selected from-OR ₃₂With-OCH ₂C (O) OR ₃₂, R wherein ₃₂Be selected from hydrogen and alkyl.

The compound of table 7-illustrative of the present invention Wherein, in table 7, R ₃₅Be selected from hydrogen and-OR ₃₆, R wherein ₃₆Be selected from hydrogen and alkyl.

The compound of table 8-illustrative of the present invention

Wherein, in table 8, R ₃₀And R ₃₅Be selected from independently of one another-OR ₃₂With-OCH ₂C (O) OR ₃₂, R wherein ₃₂Be selected from hydrogen and alkyl.

Analytical procedure

Compound of the present invention is the hair growth active substance, and is most preferably nonimmunosuppressive in these compounds.Can use following method to test the ability of compound of the present invention (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 convert (" telogen ") rest stage of the growth cycle of hair of mouse the potential of the growth phase (" anagen ") of growth cycle of hair to.

Be not wishing to be bound by theory, growth cycle of hair has three main phase: the anagen, catagen and telogen.It is believed that about 40 day age, (Indianapolis IN) had long telogen for Harlan Sprague Dawley, Inc., and this moment, hair growth occurred simultaneously to the C3H mouse in about 75 day age.It is believed that after 75 day age, hair growth occurs no longer simultaneously.During have the black fur when in hair growth experiment, the using mouse 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 topical application.Use transition detection telogen hereinafter generates by the measurement melanogen screens the compound with hair growth potentiality.

Use three groups 44 day age C3H mouse: media (Vehicle) control group, positive controls and test compounds group, wherein the administration of test compounds group is compound of the present invention.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 the melanogen formation reaction looks to be positive but when carrying out slowly, some researchs will proceed to the 24th day so.Typical research and design has been shown in the following table 9:

Table 9

Group number	Number of animals	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 SigmaChemical Co., St.Louis, MO).

It is carried out topical therapeutic (at the bottom of afterbody, extremely descending rib) from Mon-Fri at bottom back to mouse.Use transfer pipet and tube head 400 microlitres to be moved to the back of each mouse.Use 400 microlitre amounts of application lentamente, the hair on the mobile simultaneously mouse makes amount of application arrive skin.

When topical application on mouse is handled at every turn, provide the range estimation rank of the 0-4 of the skin color in the application zone of each animal.In the time of the anagen that mouse converted to from telogen, its skin color will become more bluish black.As shown in table 10 below, when skin is become when black-and-blue by white, the following visual observations result of rank 0 to 4 representative:

Table 10

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 portion of therapeutic area is covered (expression mouse anagen phase) completely by color	??4

Immunosuppression detects

The immunosuppression of this paper detects the immunosuppressive activity of having predicted The compounds of this invention.The following detection:

Dead (the CO of the peace in from 7 to 16 ages in week ₂Suffocate) bull C3H mouse (mouse 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 transfer 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 substratum, this cell culture medium constitutes (cell culture medium of having bought from Gibco-BRL) by the red RPMI1640 of reactive phenol, and it contains 10% heat-inactivated foetal calf serum (Gibco-BRL), penicillin (50U/ml), Streptomycin sulphate (100 mcg/ml), L-glutaminate (2mM), 2 mercapto ethanol (10 ^-5M) and 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 substratum 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 level is 5 mcg/ml) splenocyte is activated in the existence of test compounds or not.Test compounds is formed in stoste in the dimethyl sulfoxide (DMSO) (DMSO), and dilution and add with 50 microlitres/hole in substratum 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 counter (Packard), count.Measure the activity of the active percentage ratio 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-parametric line 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-immunosuppression test compounds thinks so that less than 2% of cyclosporin A this test compounds is non-inhibitive ability of immunity.

Use MTT (3-[4,5-dimethyl-thiazolyl-2-yl] 2,5-phenylbenzene-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(OD) of 540 nanometers under the background correction of 650 nanometers.

Anti-multiple medicines

As this paper was disclosed, compound of the present invention also was used for for example increasing antiproliferative activity and/or the prevention and/or the treatment multi-drug resistance of medicine.According to the above-mentioned performance of the described detection The compounds of this invention of following patent, described patent is: USP5, and 744,485, people such as Zelle transfer VertexPharmaceuticals Inc., and on April 28th, 1998 authorized; USP5,726,184, people such as Zelle transfer Vertex Pharmaceuticals Inc., and on March 10th, 1998 authorized; USP5,620,971, people such as Armistead transfer Vertex Pharmaceuticals Inc., and on April 15th, 1997 authorized and USP5, and 543,423, people such as Zelle transfer Vertex Pharmaceuticals Inc., and on August 6th, 1996 authorized.

The preparation method

Prepare compound of the present invention according to method known to a person of ordinary skill in the art.It is known preparing initial substance used in the compound of the present invention, prepares by known method, 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, when sheltering or protect other functional group in the compound, just 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.

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

In addition, will be appreciated that a kind of optically active isomer comprises diastereomer and enantiomer, or steric isomer, can have the character of hope than another kind of optically active isomer.Therefore, when open and protection was of the present invention, when disclosing a kind of racemic mixture, obviously plan also disclosed and protects two kinds of optical isomers, comprises diastereomer and enantiomer, or is substantially free of the steric isomer 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
		Tetrahydrofuran (THF)	THF
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride	EDAC
		The trimethyl silyl fluoroform sulphonate	TMS-OTf
N, the N-diisopropyl ethyl amine	i-Pr 2NEt or i-Pr 2EtN
		Trifluoroacetic acid	TFA
Lithium hydroxide	LiOH
		2-(tert-butoxycarbonyl oxyimino group)-2-phenylacetonitrile	Boc-ON
Phenyl (part)	Ph or ph

Embodiment 1

(1a.2-1,7-phenylbenzene-4-heptyl)-4,4-dimethyl-2-oxazoline: with 2,4,4-trimethylammonium-2-oxazoline (5.64 milliliters, 44.2 mmoles) at room temperature is dissolved in inert atmosphere among the anhydrous THF (40 milliliters).Solution is cooled to-78 ℃ and drip n-Butyl Lithium (31.3 milliliters/1.6M, in hexane, 50 mmoles).THF (20 milliliters) solution that in 10 minutes, adds 1-bromo-3-phenyl-propane (7.42 milliliters, 48.8 mmoles).Remove cooling bath, and make reaction soln arrive room temperature.After 30 minutes, again solution is cooled to-78 ℃.The dropping n-Butyl Lithium (31.3 milliliters/1.6M, in hexane, 50 mmoles).After 30 minutes, in 10 minutes, drip the solution of 1-bromo-3-phenyl-propane (7.42 milliliters, 48.8 mmoles) in THF (20 milliliters).During ensuing 12 hours, under agitation make sluggish arrive room temperature.Reactant is poured in the water (200 milliliters) and carried out acidifying, extract with ether (150 milliliters) with 1N hydrochloric acid.With the waterbearing stratum cooling, neutralize with 50% sodium hydroxide solution, and extract with ether (3 * 100 milliliters).With the ethereal extract that merges with dried over mgso, filter and carry out vacuum concentration.By the preparative chromatography on silica gel thick product is carried out purifying and obtain required Shuan alkylation De oxazoline 1a.

(1b. 1,7-phenylbenzene-4-heptyl) carboxylic acid: at room temperature oxazoline 1a (9.36 grams, 26.8 mmoles) is dissolved in the diox (100 milliliters).Add 3N hydrochloric acid (200 milliliters) and with gained solution reflux 18 hours.Solution is cooled to envrionment temperature, pours into then in the water (200 milliliters), and extract with ether (3 * 150 milliliters).The ethereal extract that merges water (75 milliliters) successively and salt solution (75 milliliters) are washed, then with dried over mgso, filter and carry out vacuum concentration, obtain required product.

1c. anti--1,2-diamino-cyclohexane, (1,7-phenylbenzene-4-heptyl) carboxylic acid amide: under inert atmosphere, carboxylic acid 1b (1.0 grams, 3.37 mmoles) is dissolved in the methylene dichloride (50 milliliters) in room temperature.Add instead-1,2-diamino-cyclohexane (0.77 gram, 6.75 mmoles) adds i-Pr subsequently ₂NEt (0.6 milliliter, 3.4 mmoles) and PyBOP (1.9 grams, 3.7 mmoles).At ambient temperature reaction mixture was stirred 18 hours, pour into then in the ethyl acetate (300 milliliters), wash successively with 0.1N hydrochloric acid (150 milliliters), saturated sodium bicarbonate solution (75 milliliters) and salt solution (50 milliliters).Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the preparative chromatography on silica gel thick product is carried out purifying and obtain required product.

1d. anti--1, the 2-diamino-cyclohexane, 1-N-(1,7-phenylbenzene-4-heptyl) carboxylic acid amide, 2-N-(3 ', 4 ', 5 '-the trimethoxyphenyl glyoxylyl) acid amides: acid amides 1c (0.73 gram, 1.83 mmoles) at room temperature is dissolved in the anhydrous methylene chloride (30 milliliters).Once add 3 ', 4 ', 5 '-trimethoxyphenyl oxoethanoic acid (0.67 gram, 2.8 mmoles), add triethylamine (0.6 milliliter, 4.3 mmoles) and EDAC (0.53 restrains 2.8 mmoles) then.At room temperature reaction mixture was stirred 18 hours, pour into then in the water (50 milliliters), and extract with methylene dichloride (3 * 40 milliliters).Use 0.1N hydrochloric acid (40 milliliters) and saturated sodium bicarbonate solution (40 milliliters) to wash successively the organic extract that merges, then on sal epsom drying, filter and carry out vacuum concentration.By the preparative chromatography on silica gel thick product is carried out purifying and obtain required product 1d.

Embodiment 2

2a. suitable-2-(N-t-butoxycarbonyl amino)-1-Cyclopentane carboxylic acid, 4-phenyl butyl acid amides: suitable-2-(N-t-butoxycarbonyl amino)-1-Cyclopentane carboxylic acid (4.1 grams, 17.7 mmoles) is dissolved among 160 milliliters of DMF.Add 4-phenyl butyl amine (2.4 grams, 16.1 mmoles) and i-Pr ₂NEt (5.6 milliliters, 32.2 mmoles) adds PyBOP (8.8 grams, 16.9 mmoles) subsequently.At room temperature reactant was stirred 19 hours, pour into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), extract with ethyl acetate (600 milliliters).Use salt solution (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and salt solution (2 * 200 milliliters) to wash successively organic layer.Organic layer is dry on sal epsom, filter and carry out vacuum concentration.By chromatography thick product is carried out purifying and obtain required acid amides 2a.

2b. suitable-2-amino-1-Cyclopentane carboxylic acid, 4-phenyl butyl acid amides: acid amides 2a (5.5 grams, 15.3 mmoles) is dissolved in 150 milliliters of anhydrous methylene chlorides.During 5 minutes, drip TFA (120 milliliters).After 2 hours, cooling mixture in ice bath, adding saturated solution of potassium carbonate is about 8 up to pH.Transfer to mixture in the separating funnel that contains methylene dichloride (200 milliliters) and water and shake.With organic layer water (200 milliliters) washing, dry on sal epsom then.Mixture is filtered and carry out vacuum concentration to obtain required amine 2b.

2c. suitable-2-(3 ', 4 ', 5 '-trimethoxyphenyl glyoxylyl amino)-the 1-Cyclopentane carboxylic acid, 4-phenyl butyl acid amides: amine 2b (3.4 grams, 13.1 mmoles) is dissolved in 150 milliliters of dry DMF.Adding 3 ', 4 ', 5 '-trimethoxyphenyl oxoethanoic acid (3.9 grams, 16.4 mmoles), add i-Pr then ₂NEt (5.7 milliliters, 32.7 mmoles) adds PyBOP (8.85 grams, 17.0 mmoles) subsequently.At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), and extracts with ethyl acetate (600 milliliters).Use salt solution (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and salt solution (2 * 100 milliliters) to wash successively organic layer.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By chromatography product is carried out purifying and obtain required acid amides 2c.

Embodiment 3

3a. suitable-1,2-diamino-cyclohexane, (1,7-phenylbenzene-4-heptyl) carboxylic acid amide: under inert atmosphere, carboxylic acid 1b (2.0 grams, 6.74 mmoles) is dissolved among the DMF (100 milliliters) in room temperature.Add suitablely-1,2-diamino-cyclohexane (1.43 grams, 12.5 mmoles) adds i-Pr subsequently successively ₂NEt (1.18 milliliters, 6.8 mmoles) and PyBOP (3.9 grams, 7.45 mmoles).At ambient temperature reaction mixture was stirred 18 hours, pour into then in the ethyl acetate (600 milliliters), wash successively with 0.1N hydrochloric acid (300 milliliters), salt solution (100 milliliters), saturated sodium bicarbonate solution (150 milliliters) and salt solution (100 milliliters).Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the preparative chromatography on silica gel thick product is carried out purifying and obtain required acid amides 3a.

3b. suitable-1,2-diamino-cyclohexane, 1-N-(1,7-phenylbenzene-4-heptyl) carboxylic acid amide, 2-N-(phenyl glyoxylyl) acid amides: acid amides 3a (1.46 grams, 3.68 mmoles) at room temperature is dissolved in the dry DMF (50 milliliters).Once add phenyl oxoethanoic acid (0.8 gram, 5.48 mmoles), add i-Pr then ₂NEt (1.5 milliliters, 8.6 mmoles) and PyBOP (2.9 grams, 5.54 mmoles).At room temperature reaction mixture was stirred 18 hours, pour into then in the ethyl acetate (300 milliliters), and use 0.1N hydrochloric acid (150 milliliters), salt solution (50 milliliters) and saturated sodium bicarbonate solution (150 milliliters) and salt solution (50 milliliters) to wash successively, dry on sal epsom then, filter and carry out vacuum concentration.By the preparative chromatography on silica gel thick product is carried out purifying and obtain required product 3b.

Embodiment 4

4a. suitable-2-(N-t-butoxycarbonyl amino)-1-cyclohexane carboxylic acid: suitable-2-amino-1-hexahydrobenzoic acid (5.0 grams, 35 mmoles) is dissolved in 40 milliliters of 1: 1 dioxanes: in the water.Add triethylamine (7.3 milliliters, 52.4 mmoles), add Boc-ON (9.5 grams, 38.4 mmoles) subsequently.Mixture was stirred 4 hours, pour into then in the water (75 milliliters), and extract with ethyl acetate (3 times, each 75 milliliters).The aqueous solution is cooled off in ice bath, and pH regulator is arrived about 2.5 with ice-cold 1N hydrochloric acid soln.The gained mixture is extracted with methylene dichloride (3 times, each 75 milliliters).The organic extract that merges is dry on sal epsom, filter and carry out vacuum concentration and obtain 4a.

4b. suitable-2-(N-t-butoxycarbonyl amino)-1-hexahydrobenzoic acid, 1,7-phenylbenzene-4-heptyl acid amides: carboxylic acid 4a (4.3 grams, 17.7 mmoles) is dissolved among 160 milliliters of DMF.Add 1, amino heptane of 7-phenylbenzene-4-(4.3 grams, 16.1 mmoles) and i-Pr ₂NEt (5.6 milliliters, 32.2 mmoles) adds PyBOP (8.8 grams, 16.9 mmoles) subsequently.At room temperature reactant was stirred 19 hours, pour into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), and extract with ethyl acetate (600 milliliters).Separate organic layer, and wash successively with salt solution (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and salt solution (2 * 200 milliliters).Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the chromatography on silica gel product is carried out purifying and obtain required acid amides 4b.

4c. suitable-2-amino-1-hexanaphthene alkane carboxylic, 1,7-phenylbenzene-4-heptyl acid amides: acid amides 4b (7.54 grams, 15.3 mmoles) is dissolved in 150 milliliters of anhydrous methylene chlorides.During 5 minutes, drip TFA (120 milliliters).After 2 hours, cooling mixture in ice bath, adding saturated solution of potassium carbonate is about 8 up to pH.Transfer to mixture in the separating funnel that contains methylene dichloride (200 milliliters) and water and shake.With organic layer water (200 milliliters) washing, dry on sal epsom then.Mixture is filtered and carry out vacuum concentration to obtain required amine 4c.

4d. suitable-2-(3 ', 4 ', 5 '-trimethoxyphenyl glyoxylyl amino)-the 1-hexahydrobenzoic acid, 1,7-phenylbenzene-4-heptyl acid amides: amine 4c (5.14 grams, 13.1 mmoles) is dissolved in 150 milliliters of dry DMF.Adding 3 ', 4 ', 5 '-trimethoxyphenyl oxoethanoic acid (3.93 grams, 16.4 mmoles) and i-Pr ₂NEt (5.7 milliliters, 32.7 mmoles) adds PyBOP (8.9 grams, 17.0 mmoles) then.At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), and extracts with ethyl acetate (600 milliliters).Separate each layer, and use salt solution (100 milliliters), saturated sodium bicarbonate solution (300 milliliters) and salt solution (2 * 100 milliliters) to wash successively organic layer.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the chromatography on silica gel product is carried out purifying and obtain required acid amides 4d.

Embodiment 5

5a.N-(phenylbenzene methylene radical)-2-amino-5-phenyl benzyl valerianate: N-(phenylbenzene methylene radical)-glycine benzyl ester (20.0 grams, 60.8 mmoles) is dissolved in 130 milliliters of acetonitriles.Add 1-bromo-3-phenyl-propane (14.5 grams, 72.8 mmoles), salt of wormwood (25.2 grams, 182.2 mmoles) and Tetrabutyl amonium bromide (1.96 restrain 6.0 mmoles) and mixture is refluxed.After 3 hours, with the mixture cool to room temperature, filter and carry out vacuum concentration.Add entry (400 milliliters) and extract mixture with ether (1.2 liters).Organic extract water (400 milliliters) and salt solution (200 milliliters) are washed, dry on sal epsom, filter and carry out vacuum concentration.By the chromatography on silica gel product is carried out purifying and obtain required ester 5a.

5b.2-amino-5-phenyl benzyl valerianate: ester 5a (24.62 grams, 55.0 mmoles) is dissolved in 1N anhydrous hydrochloric acid (600 milliliters) and the ether (200 milliliters), at room temperature stirs this mixture.After 20 hours, separate each layer, and the waterbearing stratum is extracted with ether (200 milliliters).In ice bath, cool off the waterbearing stratum, pH is adjusted to about 10 with saturated wet chemical.Mixture is extracted with methylene dichloride (3 * 300 milliliters) and salt solution (100 milliliters), dry on sal epsom then, filter and carry out vacuum concentration and obtain amino ester 5b.

5c. suitable-2-(N-t-butoxycarbonyl amino)-1-Cyclopentane carboxylic acid, benzyl 5-phenyl-2-valerate acid amides: suitable-2-(N-t-butoxycarbonyl amino)-1-Cyclopentane carboxylic acid (4.8 grams, 20.9 mmoles) is dissolved in 230 milliliters of methylene dichloride.Add amino ester 5b (5.4 grams, 19.0 mmoles) and i-Pr ₂NEt (7.0 milliliters, 39.9 mmoles) adds PyBOP (10.9 grams, 20.9 mmoles) subsequently.At room temperature reactant was stirred 18 hours, pour into then in the ice-cold 0.1N hydrochloric acid (250 milliliters), and extract with ethyl acetate (300 milliliters).Separate each layer, and (150 milliliters) and salt solution (50 milliliters) wash to organic layer to use saturated sodium bicarbonate solution successively.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the chromatography on silica gel product is carried out purifying and obtain required acid amides 5c.

5d. suitable-2-amino-1-Cyclopentane carboxylic acid, benzyl 5-phenyl-2-valerate acid amides: acid amides 5c (9.6 grams, 19.4 mmoles) is dissolved in 185 milliliters of anhydrous methylene chlorides.During 5 minutes, drip TFA (150 milliliters).After 2 hours, cooling mixture in ice bath, adding saturated solution of potassium carbonate is about 8 up to pH.Transfer to mixture in the separating funnel that contains methylene dichloride (250 milliliters) and water (250 milliliters) and shake.Separate the washing of organic layer and water (200 milliliters).Water layer is stripped with methylene dichloride (100 milliliters).The organic extract that merges is dry on sal epsom, filter and carry out vacuum concentration to obtain required amine 5d.

5e. suitable-2-(3 ', 4 ' 5 '-trimethoxyphenyl glyoxylyl amino)-the 1-Cyclopentane carboxylic acid, benzyl 5-phenyl-2-valerate acid amides: amine 5d (7.14 grams, 18.1 mmoles) is dissolved in 220 milliliters of anhydrous methylene chlorides.Adding 3 ', 4 ', 5 '-trimethoxyphenyl oxoethanoic acid (5.2 grams, 21.7 mmoles) and i-Pr ₂NEt (5.14 grams, 39.8 mmoles) adds PyBOP (11.3 grams, 21.7 mmoles) subsequently.At room temperature reaction stirred is 13 hours, pours into then in the ice-cold 0.1N hydrochloric acid (250 milliliters), and extracts with ethyl acetate (300 milliliters).Separate each layer, use saturated sodium bicarbonate solution (200 milliliters) and salt solution (50 milliliters) to wash successively organic layer.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By silica gel chromatography product is carried out purifying and obtain required acid amides 5e.

Embodiment 6

6a.N N '-dimethyl-anti--1,2-diamino-cyclohexane, 5-phenylpentanoic acid acid amides: at room temperature in inert atmosphere 5-phenylpentanoic acid acid amides (6.0 grams, 33.7 mmoles) is dissolved in the methylene dichloride (500 milliliters).Add N, N '-dimethyl-anti--1, and 2-diamino-cyclohexane (9.6 grams, 67.5 mmoles) adds i-Pr subsequently ₂NEt (5.9 milliliters, 33.9 mmoles) and PyBOP (19.3 grams, 37.1 mmoles).At room temperature stirred reaction mixture is 18 hours, pours into then in the ethyl acetate (300 milliliters), uses 0.1N hydrochloric acid (150 milliliters), saturated sodium bicarbonate solution (75 milliliters) and salt solution (50 milliliters) to wash successively.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the preparative chromatography on the silica gel thick product is carried out purifying and obtain required acid amides 6a.

6b.N N '-dimethyl-anti--1,2-diamino-cyclohexane, 1-N-5-phenylpentanoic acid acid amides, 2-N-(phenyl glyoxylyl) acid amides: at room temperature acid amides 6a (0.55 gram, 1.83 mmoles) is dissolved in the anhydrous methylene chloride (30 milliliters).Once add phenyl oxoethanoic acid (0.42 gram, 2.8 mmoles), add i-Pr subsequently successively ₂NEt (0.75 milliliter, 4.3 mmoles) and PyBOP (1.44 grams, 2.77 mmoles).At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (30 milliliters) also to extract with methylene dichloride (40 milliliters).Separate each layer, organic layer is washed with saturated sodium bicarbonate solution (30 milliliters) and salt solution (15 milliliters).By the preparative chromatography on the silica gel thick product is carried out purifying and obtain required product 6b.

Embodiment 7

7a.N, N '-dimethyl-anti--1, the 2-diamino-cyclohexane, 1-N-5-phenylpentanoic acid acid amides, 2-N-(2-furyl) glyoxamides: at room temperature with N, N '-dimethyl-anti--1, the 2-diamino-cyclohexane, 5-phenylpentanoic acid acid amides 6a (10.0 grams, 33.1 mmoles) is dissolved in the anhydrous methylene chloride (600 milliliters).Once add phenyl oxoethanoic acid (5.5 grams, 49.7 mmoles), add i-Pr subsequently successively ₂NEt (13.5 milliliters, 77.8 mmoles) and PyBOP (25.8 grams, 49.6 mmoles).At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (600 milliliters) also to extract with methylene dichloride (800 milliliters).Separate each layer, organic layer is washed with saturated sodium bicarbonate solution (600 milliliters) and salt solution (300 milliliters).By the preparative chromatography on the silica gel thick product is carried out purifying and obtain required product 7a.

Embodiment 8

8b. suitable-2-(2-butyl glyoxylyl amino)-1-hexahydrobenzoic acid, 1,7-phenylbenzene-4-heptyl acid amides: amine 4c (3.14 grams, 8.0 mmoles) is dissolved in 100 milliliters of anhydrous methylene chlorides.Add 2-butyl oxoethanoic acid (1.56 grams, 12.0 mmoles) and i-Pr ₂NEt (4.2 milliliters, 24.0 mmoles) adds PyBOP (7.3 grams, 14.0 mmoles) then.At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (100 milliliters), and extracts with ethyl acetate (150 milliliters).Separate each layer, and use saturated sodium bicarbonate solution (1500 milliliters) and salt solution (100 milliliters) to wash successively organic layer.Organic solution is dry on sal epsom, filter and carry out vacuum concentration.By the chromatography on silica gel product is carried out purifying and obtain required acid amides 8b.

Embodiment 9

9a. under agitation magnesium (40.2 grams, 1.65 moles) and anhydrous ether (ether) (3.2 liters) are incorporated in the reaction vessel.The solution of 1-bromo-3-phenyl-propane in 1.6 liters of anhydrous ethers is added in the feed 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 anhydrous ethers is put into feed 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.

9b.1, the amino heptane of 7-phenylbenzene-4-: use the reaction mixture of feed hopper with methyl alcohol (3.2 liters) dilution 9a.Add sodium borohydride (83.4 grams, 2.2 moles) several times.When reinforced finishing, reactant was at room temperature stirred 6 hours.Make the reaction 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 waterbearing stratum 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 1MHCl (1.2 liters) acidifying.Mixture was stirred 1 hour and carry out vacuum concentration.Gained throw out dilution in acetonitrile, and restir 16 hours.Filter to collect required 1, the amino heptane 9b of 7-phenylbenzene-4-.

The purposes of The compounds of this invention

The compound of this paper can be used for this class patient's condition of this class, as the alopecia of treatment Mammals, comprises prevention and/or reverse hair loss and promotes hair growth.This class patient's condition can show as alopecia, comprises the baldness of male sex's mode and the baldness of women's mode.

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

And, except the treatment alopecia, compound of the present invention can be used for the treatment of the various clinical disease, and these diseases include but not limited to: anti-multiple medicines (especially for cancer chemotherapy), nervous disorders and neurodegenerative disease, the heart and injury relevant with local asphyxia/reperfusion injury and treatment fungi, microorganism, virus (particularly HIV), malaria or other parasitic disease or the patient's condition.Compound of the present invention also can be used as the inhibitor of multidrug transporter to strengthen as pharmacokinetics and bioavailability.Some compound of the present invention can present immunity modulation character.These compounds are proving useful aspect treatment organ-graft refection and the various autoimmune disease, and above-mentioned disease includes but not limited to: behcet disease (Behcet ' s disease), regional ileitis (Crohn ' s disease), systemic lupus erythematous, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthenia gravis, insulin-dependent diabetes mellitus and Graves disease.In addition, compound of the present invention can be used for treating some inflammatory and anaphylactic disease state, comprises urticaria, allergic contact dermatitis, atopic dermatitis, atopy keratoconjunctivitis, inflammatory bowel disease and asthma.Compound of the present invention also can be used for treating the cardiac hypertrophy in the congested heart failure.

Compound of the present invention also can be united with matrix metallo-proteinase inhibitor and is used for the treatment of various diseases and comprise as disorganization's property disease, cancer and anti-multiple medicines rerum natura by the mediation of undue metal proteinase activity, and all diseases of above mentioning already of treatment.The particularly preferred matrix metallo-proteinase inhibitor that is used for this class combination comprises those that describe in the following files: U.S. Patent application serial number 60/024,765, and people such as Pikul transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,842, people such as Natchus transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,846, people such as Pikul transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,746, people such as Almstead transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,830, people such as Pikul transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,764, people such as De transfer P﹠amp; G company, on August 28th, 1996 submitted to; U.S. Patent application serial number 60/024,766, people such as Wang transfer P﹠amp; G company, on August 28th, 1996 submitted to.

Compound of the present invention preferably is mixed with pharmaceutical composition and is used for the treatment of or prevents various diseases as the aforementioned.Use the standard drug compounding process, as Remington ' s Pharmaceutical Sciences, MackPublishing Company, Easton, those that PA. (1990) is disclosed.

Usually, for being administered systemically, about 5 milligrams to about 3000 milligrams of the dosage of administration every day The compounds of this invention, 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.Be partial with the time length of the concrete dosage of compound to be administered and treatment and treatment or system be complementary.Dosage and treatment plan also depend on effect, the main body of this class factor such as used particular compound, treatment indication, compound personal characteristics (as weight, age, sex and the medical conditions of main body), with the conformability of treatment plan and treatment in the existence and the seriousness of any side effect.

Except containing compound of the present invention, composition of the present invention contains pharmaceutically useful carrier (" carrier ").Term used herein " pharmaceutically useful carrier " refers to that one or more are fit to deliver medicine to mammiferous compatible solid or liquid filler thinner or encapsulate material.Term used herein " compatible " refers to that each component of composition can be in one way and compound blending of the present invention, blending each other, and described mode should make the reaction that reduces the effect of composition under common service condition basically.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 Mammals.Carrier itself can be that inert or its can have the pharmacy benefit of himself.

It is suitable that composition of the present invention can be, 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 especially preferred.Depend on required specific administration approach, can use multiple pharmaceutically useful carrier well known in the art.These comprise solid or liquid filler, thinner, hydrotropic agent, tensio-active agent 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 compound should be enough to provide the practical substances amount to administration per unit dosage compound.The technology and the composition of used preparation formulation in the inventive method described: Modem Pharmaceutics, the 9th and 10 chapters, Banker ﹠amp 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 W-Gum and potato starch; Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and methylcellulose gum; The atomizing tragacanth gum; Fructus Hordei Germinatus; Gelatin; Talcum; Solid lubricant such as stearic acid and Magnesium Stearate; Calcium sulfate; Vegetables oil such as peanut oil, Oleum Gossypii semen, sesame oil, sweet oil, Semen Maydis oil and theobroma oil; Polyvalent alcohol such as propylene glycol, glycerine, sorbyl alcohol, mannitol and polyoxyethylene glycol; Alginic acid; Emulsifying agent such as TWEENS; Wetting agent such as Sodium Lauryl Sulphate BP/USP; Tinting material; Seasonings; Tablet agent, stablizer; Antioxidant; Sanitas; No pyrogene water; Isotonic saline solution and phosphate buffered saline buffer.

The selection of uniting the pharmaceutically useful carrier of use with compound of the present invention is determined by the route of administration of compound basically.

Particularly, the pharmaceutically acceptable carrier that is used for systemic administration comprises sugar, starch, Mierocrystalline cellulose and derivative thereof, Fructus Hordei Germinatus, gelatin, talcum, calcium sulfate, vegetables oil, synthetic oil, polyvalent alcohol, alginic acid, phosphate buffered saline buffer, emulsifying agent, isotonic saline solution and does not have pyrogene water.The used preferred vector of parenterai administration comprises propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.Preferably, the pharmaceutically useful carrier in the composition of parenterai administration account for whole composition weight at least about 90%.

Multiple oral dosage form be can use, this class solid form such as tablet, capsule, granule and loose powder agent comprised.These oral dosage forms comprise safe and effective amount, usually at least about 5%, and preferred about 25% to about 50% compound of the present invention.Tablet can be compacted, compressing tablet is developed, is surrounded by enteric coating, sweet tablet, film coating or multiple compacting, wherein contains suitable binding agent, lubricant, thinner, disintegrating agent, tinting material, seasonings, flow-induction agent and fusing agent.Liquid oral dosage form comprises the aqueous solution, emulsion, suspension, by reconstituted solution of non-effervescive particle and/or suspension, by the reconstituted effervescent formulation of effervescent granule, it contains suitable solvent, sanitas, emulsifying agent, suspension agent, thinner, sweetener, fusing agent, tinting material and seasonings.

The pharmaceutically useful carrier that is applicable to the unit dosage 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 lime carbonate, yellow soda ash, mannitol, lactose and Mierocrystalline 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 glidant (glidants) to improve the flow characteristics of powdered mixture as silicon-dioxide.Can add tinting material such as FD ﹠amp; The C dyestuff improves outward appearance.Sweetener and seasonings such as aspartame, asccharin, menthol, peppermint and fruit condiment are as the adjuvant of chewable tablets.Capsule (comprising that the time discharges and sustained release preparation) comprises above-mentioned disclosed one or more solid diluents usually.Auxiliary Consideration such as taste, cost and stability in storage 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 liquor, emulsion, suspension, powder, particle, 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, glycerine, propylene glycol, polyoxyethylene glycol, liquid sugar, sorb alcohol and water.For suspension, typical suspension agent comprises methylcellulose gum, Xylo-Mucine, AVICEL RC-591, tragacanth gum and sodiun alginate; Typical wetting agent comprises Yelkin TTS and Spheron MD 30/70 (polysorbate 80); Typical preservatives comprises para methyl paraben and Sodium Benzoate.Also can comprise one or more components sweetener as indicated above, seasonings and tinting material by oral liquid composition.

This based composition also can pass through the ordinary method dressing, usually the dressing with pH or time-dependent manner carries out, and makes like this to discharge or discharge to prolong required effect in the different time near the gi tract of compound of the present invention required local use location.This class formulation generally includes but is not limited to one or more cellulose ethanoate phthalic esters, poly-acetate O-phthalic vinyl acetate (polyvinylacetate phthalate), hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit dressing, wax and lac.

Be used to realize that other composition of systematicness transmission The compounds of this invention comprises hypogloeeis, cheek and nose formulation.This based composition comprises one or more soluble packing materials such as sucrose, sorbyl alcohol and mannitol usually; Binding agent such as Acacia, Microcrystalline Cellulose, carboxymethyl cellulose and Vltra tears.Also can comprise above disclosed glidant, lubricant, sweetener, tinting material, antioxidant and seasonings.

Compound of the present invention also can pass through topical.The carrier of topical composition preferably has and helps compound of the present invention and infiltrate through in the skin with in the surrounding environment that arrives hair follicle.Topical composition of the present invention can be any form and comprise as solution, white cream, ointment, gel, dew (lotion), shampoo, leave and rinsing type hair conditioner, milk liquid, sanitising agent, wetting Agent for Printing Inks, sprays, transdermal patches (skin patch) etc.

Contain active compound topical composition can with variety carrier material well known in the art blend, described carrier substance such as water, alcohols, Aloe gel, wallantoin, glycerine, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 Tetradecyl propionate etc.

Other material that is applicable to topical carrier comprises as softener (emollient), solvent, wetting Agent for Printing Inks, thickening material and powder.The example of each is as follows in the material of a little types of fortune that can use separately or use as the mixture of one or more materials:

Softener, as stearyl alcohol, single ricinolic acid glyceryl ester, glyceryl monostearate, propane-1, the 2-glycol, butane-1, the 3-glycol, ermine oil, hexadecanol, the Unimac 5680 isopropyl ester, stearic acid, the palmitinic acid isobutyl ester, Standamul 7061, oleyl alcohol, isopropyl laurate, lauric acid hexyl ester, decyl oleate, octadecane-2-alcohol, different hexadecanol, cetin, dimethyl polysiloxane, n-butyl sebacate, Isopropyl myristate, Wickenol 111, isopropyl stearate, butyl stearate, polyoxyethylene glycol, triglycol, lanolin, sesame oil, Oleum Cocois, peanut oil, Viscotrol C, the lanosterol of ethanoylization, oil, mineral oil, butyl myristate, Unimac 5680, palmitinic acid, the linolic acid isopropyl ester, Lauryl lactate, Tetradecyl lactate, decyl oleate and Tetradecyl tetradecanoate; Propelling agent is as propane, butane, Trimethylmethane, dme, carbonic acid gas and nitrous oxide; Solvent is as ethanol, methylene dichloride, Virahol, Viscotrol C, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF); Wetting Agent for Printing Inks is as collagen, dibutyl phthalate and the gelatin of glycerine, sorbyl alcohol, 2-Pyrrolidone-5-carboxylic acid sodium, solubility; Powder is as the magnesium aluminum silicate of chalk, talcum, Fuller's earth, kaolin, starch, natural gum (gum), colloid silica, sodium polyacrylate, tetra-allkylammonium terre verte, trialkyl aryl terre verte, chemical modification, organically-modified illiteracy unsticking soil, pure aluminium silicate, pyrogenic silica, carboxyvinyl polymer, Xylo-Mucine and the ethylene glycol monostearate of hydration.

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 phosphatide.The local liposome of describing in used preferred formulation use of 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: I. and uses the mouse skin that does not have hair to carry out in vitro study to the part " S.T.P.Pharma 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, USP4,911,928, transfer Micro-Pak, Inc., authorize March 27 nineteen ninety.

Compound of the present invention also can pass through iontophoresis (iontophoresis) administration.Referring to, as, www.unipr.it/arpa/dipfarm/erasmus/erasm 14.html, people such as Banga, " be used for transmitting the iontophoretic treatment transport unit based on hydrogel of peptide/pharmaceutical grade protein " through skin, Pharm.Res., the 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, " be used for the modern iontophoresis that part drug transmits ", Int.J.Pharm, the 123rd volume, 159-171 (1995), people such as Green, " transmit a series of tripeptides " through the outer iontophoresis of skin volume, Pharm.Res., the 8th volume, 1121-1127 page or leaf (1991), people such as Jadoul, " fentanyl (Fentanyl) that transmits by the iontophoresis 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 skin iontophoresis ", Pharm.Res., the 14th (1) volume, 63-66 page or leaf (1997), people such as Santi, " gegenion electric osmose therapy-decision electric osmose mobile parameter: I.pH and ionic strength ", J.Control.Release, the 38th volume, 159-165 page or leaf (1996), people such as Santi, " gegenion electric osmose therapy-decision electric osmose mobile parameter: the II. electrode vessel is formed ", J.Control.Release, the 42nd volume, 29-36 page or leaf (1996), people such as Rao, " non-infringement glucose monitoring in gegenion 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 thyrocalcitonin ", J.Pharm.Pharmacol., the 46th volume by iontophoresis, 725-730 page or leaf (1994), people such as Volpato, " strengthening the transmission of acyclovir ", Pharm.Res. through nude mice skin by electricity repulsion and electric osmose iontophoresis, the the 12nd (11) volume, 1623-1627 page or leaf (1995).

Composition 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 compound of the present invention.The active reinforcing agent of particular type comprises other 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 compound of the present invention.These other optional hair growth stimulant (if existence) amount ranges in composition 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.

Vasodilator such as potassium channel activator, comprise for example minoxidil (minoxidil) and minoxidil derivative such as aminexil and as following file in describe those: USP3,382,247, USP5,756, on May 26th, 092,1998 authorized, USP5, on June 30th, 772,990,1998 authorized, USP5,760,043, on June 2nd, 1998 authorized, USP5,328, on July 12nd, 914,1994 authorized, USP5,466,694, authorize November 14 nineteen ninety-five, USP5,438,058, authorize and USP4 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 USP5 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 prostate cancer ", and cyproterone acetate, the USP5 that nonane diacid and derivative thereof and on January 2nd, 1996 authorize, 480, those compounds of describing in 913, those materials of describing in flutamide (flutamide) and the following patent: USP5,411,981, authorize May 2 nineteen ninety-five; USP5, on October 15th, 565,467,1996 authorized; And USP4,910,226, 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 immunosuppressor or non-immunosuppressant are as 1) S-Neoral 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 analogue, 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 Degenhardt, 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 antiseptic-germicide, as selenium sulfide, KETOKONAZOL, triclocarban (triclocarbon), Triclosan (triclosan), 2-mercaptopyridine zinc oxide (zinc pyrithione), itraconazole (itraconazole), Asiatic Acid (asiatic acid), hinokitiol, mipirocin and EPA0,680, those that describe in 745 (introducing the present invention as a reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and Minocycline HCl (minocyclin).

Antiphlogistic drug also can be used as optional hair growth stimulant and adds in the composition of the present invention.The example of suitable antiphlogistic drug can comprise glucocorticosteroid such as hydrocortisone, furoic acid momisone and Ultracortene-H, non-steroidal anti-inflammatory drug comprises cyclooxygenase or lipoxidase inhibitor, as U.S. Pat P5,756, those that describe in 092, and those compounds of describing in benzydamine (benzydamine), Whitfield's ointment and the following files: EPA0,770,399 (on May 2nd, 1997 is open); WO94/06434 (on March 31st, 1994 is open) and FR2,268,523 (on November 27th, 1975 is open) are introduced the present invention as a reference with all these files.

Another kind of suitable optional hair growth stimulant is Triiodothyronine and derivative and analogue.The example that is applicable to Triiodothyronine 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 retinoid.Suitable retinoid comprises isotretinoin (isotretionoin), Etretin (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 composition 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 flavine (flavinoids), ascomycin derivative and analogue, 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: USP5,529,769, JP10017431, WO95/35103, USP5,468,888, JP09067253, WO92/09262, JP62093215, USP5,631,282, USP5,679,705, JP08193094, angle glucoside (saponins), as EP0,558,509 (people such as Bonte), open and WO97/01346 on September 8th, 1993 people such as () Bonte, those that describe on January 16th, 1997 open (these two files are introduced the present invention as a reference), proteoglycan enzyme or glycosaminoglycan enzyme inhibitors such as USP5,015,470, on May 14th, 1991 authorized, USP5,300, on April 5th, 284,1994 authorized and USP5, and 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 promotor, analogue or inhibitor such as interleukin 1 inhibitor, interleukin-6 inhibitor, interleukin 10 promotor and tumor necrosis factor inhibitors, VITAMIN such as novel vitamin D analogues and pth antagonist, vitamin B12 analogue and panthenol, interfuron agonist and antagonist, alcohol acid such as USP5,550, described in 158 those, benzophenone and glycolylurea anticonvulsive drug such as Phenytoin Sodium Salt (phenytoin).

Other additional hair growth stimulant is described in detail in the following files: JP09-157, 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; JP62-93215, people such as Okazaki, on April 28th, 1987 is open; USP4,987,150, people such as Kurono, on January 22nd, 1991 authorized; JP290811, people such as Ohba, on October 15th, 1992 is open; JP05-286,835, people such as Tanaka, on November 2nd, 1993 is open; FR 2,723,313, Greff, and on August 2nd, 1994 is open; USP5,015,470, people such as Gibson, on May 14th, 1991 authorized; USP5, on September 24th, 559,092,1996 authorized; USP5, on July 16th, 536,751,1996 authorized; USP5, on February 3rd, 714,515,1998 authorized; EPA0, on June 14th, 319,991,1989 is open; EPA0, on October 6th, 357,630,1988 is open; EPA0, on December 8th, 573,253,1993 is open; JP61-260010, on November 18th, 1986 is open; USP5, on June 30th, 772,990,1998 authorized; USP5, on October 1st, 053,410,1991 authorized; USP4, on August 2nd, 761,401,1988 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 composition 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-Hydroxyoctanoic acid, third-1-alcohol, 1, the 4-diox, tetrahydrofuran (THF), fourth-1, the 4-glycol, propylene glycol dipelargonate, polyoxy propylidene 15 stearyl ethers, octanol, the POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, Octyl adipate, Octyl adipate, hexanodioic acid two caprinoyl esters, Wickenol 116, Wickenol 117, Uniflex DBS, ethyl sebacate, dimethyl sebacate, dioctyl sebacate, the suberic acid dibutylester, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl hexanoate, salicylic ether, Wickenol 111, Laurate ethyl, n-nonanoic acid 2-ethyl-polyhexamethylene, the Unimac 5680 isopropyl ester, butyl laurate, peruscabin, butyl benzoate, lauric acid hexyl ester, ethyl decylate, ethyl octylate, butyl stearate, benzyl salicylate, 2 hydroxy propanoic acid, the 2-Hydroxyoctanoic acid, dimethyl sulfoxide (DMSO), N, the N-N,N-DIMETHYLACETAMIDE, 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, compound of the present invention can be individually dosed or with the form administration of mixture, composition of the present invention may further include additional medicine or the vehicle that is applicable to indication.

Composition embodiment

Following composition and method embodiment are not restriction the present invention, but provide the guidance for preparing and use compound of the present invention, composition and method to those of ordinary skill.In each embodiment, the The compounds of this invention except the compound of being mentioned can be substituted in an embodiment, and has similar result.

Embodiment A

The tablet of preparation oral administration according to the present invention, it comprises:

Component	Consumption
		The compound of embodiment 3	15 milligrams
Lactose	120 milligrams
		W-Gum	70 milligrams
Talcum	4 milligrams
		Magnesium Stearate	1 milligram

Suffering from the female patient of heavy 60 kilograms (132 pounds) of rheumatoid arthritis treats with method of the present invention.Concrete scheme is to give 3 of patient's oral administration above-mentioned compositions every day, administration 2 years.

Embodiment B

Prepare topical drug delivery composition of the present invention, it comprises:

Component	Consumption
		The compound of embodiment 1	5％
Ethanol	57％
		Propylene glycol	19％
Different Sorbic Acid dimethyl ester	19％

Male sex'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 C

According to people such as Dowton, " liposome composition transmits the influence of the cyclosporin A of encapsulate to the part: I. uses 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 compound of embodiment 4 to replace cyclosporin A and use Novasome1 to form as the nonionic liposome preparing the topical drug delivery composition according to the present invention.

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

Embodiment D

Preparation is according to shampoo of the present invention, and it comprises:

Component	Embodiment C-1	Embodiment C-2	Embodiment C-3	Embodiment C-4
					Lauryl sulfate amine	11.5％	11.5％	9.5％	7.5％
Lauryl polyethenoxy ether sodium sulfate	4％	3％	2％	2％
					Coconut monoethanol amide	2％	2％	2％	2％
Unister E 275	2％	2％	2％	2％
					Hexadecanol	2％	2％	2％	2％
Stearyl alcohol	1.2％	1.2％	1.2％	1.2％
					Glycerine	1％	1％	1％	1％
Polyquaternium?10	0.5％	0.25％	-	-
					Polyquaternium??24	-	-	0.5％	0.25％
Sodium-chlor	0.1％	0.1％	0.1％	0.1％
					The sucrose polyester of cotton acid lipid acid	3％	3％	-	-
The sucrose polyester of docosoic acid lipid acid	2％	3％	-	-
					Polydimethylsiloxane	-	-	3％	2％

Cocounut oil aminopropyl trimethyl-glycine	?-	?1％	?3％	?3％
					Lauryl dimethyl amine oxide	?1.5％	?1.5％	?1.5％	?1.5％
The decyl poly-dextrose	?-	?-	?1％	?1％
					The DMDM glycolylurea	?0.15％	?0.15％	?0.15％	?0.15％
The compound of embodiment 2	?2％	?-	?-	?-
					The compound of embodiment 6	?-	?5％	?-	?-
The compound of embodiment 7	?-	?-	?3％	?-
					The compound of embodiment 5	?-	?-	?-	?6％
Phenoxyethyl alcohol	?0.5％	?0.5％	?0.5％	?0.5％
					Spices	?0.5％	?0.5％	?0.5％	?0.5％
Water	In right amount	In right amount	In right amount	In right amount

Claims (10)

1. compound is characterized in that array structure down:

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

(a) Z is saturated or undersaturated 4-, 5-, 6-, 7-, 8-or 9-person's carbocyclic ring or a heterocycle, and wherein heterocycle contains one or more O of being selected from, N, S, S (O), S (O) ₂And the heteroatoms of P ((O) OK);

(b) V is-CU-, and wherein U is selected from hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(c) G be selected from zero, O, S and NR ₁₇

(d) K is selected from hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(e) R ₁Be selected from alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl;

(f) W be selected from zero, hydrogen and low alkyl group;

(g) A is selected from the zero-sum alkyl;

(h) X and Y are selected from C (O), P (O), N, O and S independently of one another, wherein:

(i) when X is C (O), R so ₃Be zero and Y be selected from N, O and S;

(ii) when X is P (O), R so ₃Be zero and Y be selected from N and O;

(iii) when X is N, R so ₃Be selected from hydrogen, alkyl and aralkyl, Y is selected from C (O) and P (O) and R ₂Be zero;

(iv) when X is O, R so ₃Be zero, Y is selected from C (O) and P (O) and R ₂Be zero;

(v) when X is S, R so ₃Be zero, Y is C (O) and R ₂Be zero;

(f) R ₂And R ₃Be selected from zero independently of one another, hydrogen, alkyl and aralkyl;

(g) R ₄It is alkyl;

(h) R ₅And R ₆Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl with at least two carbon atoms; Or R wherein ₅And R ₆Be joined together to form carbocyclic ring or heterocycle; R wherein ₅And R ₆In at least one be not zero or hydrogen;

(i) R ₇, R ₈, R ₉And R ₁₀Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, halogen, cyano group, hydroxyl, oxo, imino-,-R ₁₄SR ₁₅,-R ₁₄S (O ₂) R ₁₅,-R ₁₄S (O) R ₁₅,-R ₁₄C (O) R ₁₅,-R ₁₄C (O) NR ₁₅R ₁₆,-R ₁₄C (O) OR ₁₅,-R ₁₄OR ₁₅,-R ₁₄NR ₁₅R ₁₆,-R ₁₄P (O) NR ₁₅R ₁₆,-R ₁₄P (O) OR ₁₅R ₁₆With the volution part, and R wherein ₇And R ₈Can choose wantonly and be joined together to form aromatics or saturated, carbocyclic ring or heterocycle, wherein this ring is fused on the Z;

(j) R ₁₄And R ₁₅Be selected from zero independently of one another, hydrogen, alkyl, alkenyl, assorted alkyl, heterochain thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, aromatic yl alkenyl and heteroaryl alkenyl; With

(k) R ₁₆And R ₁₇Be selected from hydrogen and alkyl independently of one another.

2. the compound of claim 1, wherein Z is 5-, 6-or 7-person's carbocyclic ring or a heterocycle.

3. claim 1 or 2 compound, wherein Z is 5-person's carbocyclic ring or a heterocycle.

4. claim 1 or 2 compound, wherein Z is 6-person's carbocyclic ring or a heterocycle.

5. according to each compound in the aforementioned claim, wherein G is-NH-, and A is zero, and X is C (O), and Y is N and R ₂Be hydrogen.

6. according to each compound in the aforementioned claim, wherein R ₈, R ₉And R ₁₀Be selected from zero-sum hydrogen independently of one another.

7. each compound, wherein R among the claim 1-5 ₇And R ₈Be joined together to form 5-, 6-or 7-person's carbocyclic ring or heterocyclic aromatic ring, wherein said ring is fused on the Z.

8. composition is characterized in that the compound and the pharmaceutically useful carrier of aforementioned each claim.

9. a method for the treatment of alopecia comprises the composition to aforementioned each claim of Mammals administration.

10. the treatment or the method for preventing anti-multiple medicines comprise to each composition of the aforementioned claim of Mammals administration.