CN1367678A - Method of treating hair loss using ketoamides - Google Patents

Abstract

The present disclosure describes methods for treating hair loss is mammals, including arresting and/or reversing hair loss and promoting hair growth. The methods comprise administering a compound having a structure as of formula (I) and a pharmaceutically-acceptable carrier.

Description

Use the method for keto-amide treatment alopecia

Invention field

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

Cross-index

According to the 35th of United States code the 119th (e), the application is a priority with the provisional application serial number 60/102,458 of JIUYUE in 1998 submission on the 30th.

Background technology

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

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

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

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

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

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

FK506 is the complicated macrocycle molecule with following array structure:

People such as Stocks, and " the excision of FK-506 in conjunction with the territory in in conjunction with the substituent contribution of pyranoside ", Bioorganic ﹠amp; Medicinal Chemistry Letters, the 4th volume, the 12nd phase, 1457-1460 page or leaf (1994).Disclose and had the very similar analog that should the complexity macro ring that the hair growth performance is for example alopecia bunch and/or male baldness form.Referring to, as people such as Kawai, 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., people such as order mandate in October 4 in 1994 and Rupprecht, USP5,550,233, transfer Merck; Co., Inc., on August 27th, 1996 authorized.

But, relate to the active excitement of hirsutism of cyclosporin A and FK506, to a certain extent, calmed down not as the shortage of the report of the immunosuppressant of littler, the non-macro ring FK506 complexity, various and non-immunosuppressive compounds hirsutism by relevant structure.Referring to, people such as Steiner, WO 96/40140, transfers Guilford Pharmaceuticals, Inc., December disclosed on the 19th in 1996; People such as Hamilton, WO 96/40633, transfers Guilford Pharmaceuticals, Inc., December disclosed on the 19th in 1996; People such as Steiner, USP5,696,135, transfer GPI NIL Holdings, Inc., December was authorized on the 9th in 1997; 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., December disclosed on the 10th in 1992; 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., JIUYUE was authorized on the 9th in 1997; People such as Andres, " analog that the conformation of prolineamide limits, trans prolyl peptide mimicry ", Journal of Organic Chemistry, the 58th volume, 6609-6613 page or leaf (1993); With people such as Armistead, " design of the non-macrocyclic hcv inhibitors of FKBP12, synthetic and structure are used for the mainly conjugated protein of immunosuppressant FK506 ", ActaCrystallographica, D51,522-528 page or leaf (1995).

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

Summary of the invention

The present invention relates to be used for the treatment of the method for alopecia, the method of described treatment alopecia comprises the chemical compound that is specially adapted to treat the mammal alopecia that the administration inventor finds, the alopecia of described treatment mammal comprises prevention and/or reverse hair loss and promotes hair growth.The chemical compound that is used for the inventive method has following array structure: But and the amide of pharmaceutically useful salt, hydrate and biological hydrolysis, ester and inferior amide, wherein substituent X, J, K, A, B, D, Q and m are as defined herein.

Detailed Description Of The Invention

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

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

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

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

The definition of term and use

Hereinafter be the definition of term used herein:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Method of the present invention

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

(a) have the chemical compound of following structure:

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

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

(ii) A is selected from CH ₂, O and NR ₁

(iii) R ₁Be selected from hydrogen and alkyl; (iv) J is selected from hydrogen, C ₁-C ₆Alkyl, C ₃-C ₆The C that alkenyl, benzyl, Ar replace ₁-C ₆The C that alkyl, Ar replace ₃-C ₆The C that alkenyl, Ar replace ₃-C ₆Alkynyl; K is selected from C ₁-C ₆The C that alkyl, Ar replace ₁-C ₆The C that alkyl, Ar replace ₂-C ₆The C that alkenyl, Ar replace ₂-C ₆Alkynyl and cyclohexyl methyl; Perhaps J and K can be joined together to form 5-, 6-or 7-unit heterocycle, and wherein this ring can randomly comprise and is selected from other following hetero atoms: O, S, S (O), S (O) ₂, NH and NE, wherein replace or during unsubstituted tetrahydronaphthalene part, J and K can randomly be joined together to form 5-or 6-unit and the condensed carbocyclic ring of phenyl ring when B and D are joined together to form; (v) X is selected from hydrogen, C ₁-C ₉Alkyl, C ₂-C ₉Alkenyl, C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, Ar ,-OR ₂, [C ₁-C ₄Alkyl]-Y, [C ₂-C ₄Alkenyl]-Y, Y and-NR ₃R ₄(vi) R ₂, R ₃, R ₄, B, D and E be selected from zero independently of one another, hydrogen, Ar, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Alkyl, C ₅-C ₇The C of cycloalkyl substituted ₃-C ₆Alkenyl, C ₅-C ₇The C of cycloalkyl substituted ₃-C ₆Alkynyl, C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₃-C ₆Alkenyl, C ₅-C ₇The C that cycloalkenyl group replaces ₃-C ₆The C that alkynyl, Ar replace ₁-C ₆The C that alkyl, Ar replace ₃-C ₆The C that alkenyl, Ar replace ₃-C ₆Alkynyl; One or more CH in alkyl, alkenyl and the alkynyl wherein ₂Part can randomly be selected from following hetero atom and be replaced; O, S, S (O), S (O) ₂And NR, wherein R is selected from hydrogen, C ₁-C ₄Alkyl, C ₃-C ₄Alkenyl, C ₃-C ₄Alkynyl and C ₁-C ₄Bridge joint alkyl, its jackshaft are at the N of NR and contain and form between the carbon atom in heteroatomic alkyl, alkenyl or the alkynyl forming bridged ring, and wherein the bridge joint ring randomly condenses with Ar; Wherein B and D can also be joined together to form 5-, 6-or 7-unit carbocyclic ring, and this encircles randomly with aryl-condensed; Wherein B and D can also be independently of one another:

Wherein Z is selected from hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl; V is selected from 5-, the 6-of Ar and replacement or 7-unit carbocyclic ring, and it has and is independently selected from following substituent group: oxo, hydrogen, hydroxyl, O-(C ₁-C ₄Alkyl) and O-(C ₂-C ₄Alkenyl); Wherein B also can be T, shows structure under wherein T has:

X wherein ₂Be selected from O and NR ₁₀, R wherein ₁₀Be selected from hydrogen, C ₁-C ₆Alkyl and C ₁-C ₆Alkenyl; R ₉Be selected from phenyl, benzyl, C ₁-C ₅Alkyl, C ₁-C ₅The C that alkenyl, phenyl replace ₁-C ₅The C that alkyl, phenyl replace ₁-C ₅Alkenyl; Wherein when B was T, D was R so ₈, R wherein ₈Be selected from randomly by C ₁-C ₈The C of cycloalkyl substituted ₁-C ₈Alkyl, and Ar; And R wherein ₃And R ₄Also can connect together and form 5-, 6-or 7-heterolipid family of unit or aromatic ring; (vii) Ar and Y are selected from phenyl independently of one another, benzyl, the 1-naphthyl, the 2-naphthyl, indenyl, the azulene base, fluorenyl, anthryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, the 2-pyrazolinyl, pyrazolidinyl isoxazolyl, different triazolyl, 1,2,3-oxadiazole base, 1,2, the 3-triazolyl, 1,3, the 4-thiadiazolyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, 1,3, the 5-triazine radical, the trithiane base, the indolizine base, indyl, isoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thio-phenyl, the 1H-indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, 1,2,3, the 4-tetrahydric quinoline group, isoquinolyl, 1,2,3, the 4-tetrahydro isoquinolyl, cinnolinyl, 2, the 3-phthalazinyl, quinazolyl quinoxalinyl, 1, the 8-phthalazinyl, pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl phenoxazine group, the 2-pyrrolinyl, the 3-pyrrolinyl, pyrrolidinyl, 1, the 3-dioxolyl, imidazolidinyl, the 2H-pyranose, the 4H-pyranose, piperidyl, 1, the 4-alkyl dioxin, morpholinyl, 1,4-dithiane base, thio-morpholinyl, piperazinyl, quininuclidinyl; Wherein have one or more following substituent groups that are independently selected from the Ar: hydrogen, halogen, hydroxyl, nitro ,-SO ₃H, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, O-(C ₁-C ₆Alkyl), O-(C ₂-C ₄Alkenyl), O-benzyl, O-phenyl, 1, the 2-methylene-dioxy ,-NR ₅R ₆, carboxyl, N-(C ₁-C ₅Alkyl) carboxylic acid amides, N-(C ₃-C ₅Alkenyl) carboxylic acid amides, N, N-two-(C ₁-C ₅Alkyl) carboxylic acid amides, N, N-two-(C ₃-C ₅Alkenyl) carboxylic acid amides, N-morpholino carboxylic acid amides, N-benzyl carboxylic acid amides, N-thiomorpholine are for carboxylic acid amides, N-pyridine formoxyl carboxylic acid amides, morpholinyl, piperidyl, O-M, CH ₂-(CH ₂) _q-M, O-(CH ₂) _q-M, (CH ₂) _q-O-M and CH=CH-M; R wherein ₅And R ₆Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl and benzyl, perhaps R ₅And R ₆Can be joined together to form 5-or 6-unit heterocycle; M is selected from 4-methoxyphenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, pyranose (pyrazyl), quinolyl, 3,5-dimethyl isoxazole base (dimethylisoxazoyl), isoxazolyl (isoxazoly), 2-methylthiazol base, thiazolyl, 2-thienyl, 3-thienyl and pyrimidine radicals; Q is 0 to 2 integer; And wherein Y has one or more following replacements that are independently selected from

Base: hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Alkyl, C ₁-

C ₆Alkenyl, O-(C ₁-C ₄Alkyl), O-(C ₂-C ₄Alkenyl), O-benzyl, O-phenyl, 1,2-

Methylene-dioxy, amino and carboxyl;

(vii) m is 0 to 3 integer; And

(b) pharmaceutical carrier.

The X part

The chemical compound that is used for the inventive method comprises that one is connected to the part on the described diketone amide moieties, is called X part or X herein.X is selected from hydrogen, C ₁-C ₉Alkyl, C ₂-C ₉Alkenyl, C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, Ar ,-OR ₂, [C ₁-C ₄Alkyl]-Y, [C ₂-C ₄Alkenyl]-Y, Y and-NR ₃R ₄As indicated above, all parts can be to replace or unsubstituted, but when wherein X was the cycloalkyl that replaces or cycloalkenyl group, the preferred substituted on described X partly encircles was C ₁-C ₄Alkyl or hydroxyl or C ₂-C ₄Alkenyl.Ar, R ₂, Y, R ₃And R ₄As described in other parts of the present invention.When X was Ar, preferred Ar partly was selected from phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, imidazole radicals, indyl, isoindolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl and 1,2,3,4-tetrahydric quinoline group.Illustrated as the present invention, all parts can be that replace or unsubstituted, but when X was the Ar that replaces, preferred substituted comprised hydroxyl, nitro, trifluoromethyl, C so ₁-C ₆Alkyl, O-[C ₁-C ₆Alkyl], halogen ,-SO ₃H and-NR ₅R ₆, R wherein ₅And R ₆As indicated above.Preferred X partly is selected from 3,4,5-trimethoxyphenyl, isopropyl, phenyl, the tert-butyl group, thio-phenyl-2-base, 3-benzyl oxy phenyl, 3-pi-allyl oxygen phenyl, 2-furyl and 3-isopropyl phenyl.Most preferred X partly is 3,4, the 5-trimethoxyphenyl.

J and K part

J and K part can have aforesaid structure independently of each other, perhaps can be joined together to form 5-, 6-or 7-unit heterocycle as mentioned above, and this heterocycle randomly contains other and is selected from O, S, S (O) and S (O) ₂, NH and NE hetero atom.When being joined together to form, B and D replace or during unsubstituted tetrahydronaphthalene part, J and K can randomly be joined together to form and condensed 5-of phenyl ring or 6-unit carbocyclic ring.Be used for replacement of the present invention or unsubstituted tetrahydronaphthalene partly is: R wherein ₆₁, R ₆₂And R ₆₃Be selected from hydrogen, halogen, alkyl, O-alkyl, (CH independently of one another ₂) b-aryl and R ₅₀(CH ₂) _b-aryl, wherein R ₅₀Be selected from O, S and NR ₅₁R wherein ₅₁Be selected from alkyl and hydrogen; B is 0 to 4 integer; R ₆₄Be selected from hydrogen and (CH ₂) _c-R ₅₂, R wherein ₅₂Be selected from aryl and NR ₅₃R ₅₄, R wherein ₅₃And R ₅₄Be selected from hydrogen, alkyl and (CH independently of one another ₂)-aryl, perhaps R wherein ₅₃And R ₅₄Be joined together to form 5-or 6-unit heterocycle; C is 1 to 3 integer.

When J and K formation heterocycle, this encircles preferably 5-or 6-unit ring.When J and K formation heterocycle, preferred any other hetero atom that does not comprise any non-Q nitrogen-atoms in the 1-position of encircling shown in this paper of this ring.

The A part

A is selected from CH ₂, O, S and NR ₁, R wherein ₁As described herein.Preferably, A is selected from O and NR ₁Most preferably, A is NR ₁In these cases, R ₁Most preferably be hydrogen.

B and D part

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

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

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

Integer m

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

Preferred Ar part

The Ar part as defined herein.Preferred Ar partly is selected from phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, imidazole radicals, indyl, isoindolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, 2-furyl and 1,2,3, the 4-tetrahydric quinoline group, wherein Ar has one or more following substituent groups that are independently selected from: hydrogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkyl, O-[C ₁-C ₆Alkyl], halogen ,-SO ₃H and-NR ₅R ₆, R wherein ₅And R ₆As indicated above.

The preferred chemical compound that is used for the inventive method is as shown in the table:

Table 1

Wherein G, L and M are selected from CH independently of one another ₂, S, O, NH and NE, wherein the definition of E is as indicated above.

Table 2

R wherein ₈, R ₉And R ₁₀Definition as indicated above.

Other chemical compound that is preferred for the inventive method comprises that wherein B and D are joined together to form and the condensed 5-of aromatic ring, 6-or 7-unit ring, as:

Wherein

(a) R ₁₂Be selected from hydrogen and (CH ₂) _t-R ₁₆, wherein t is 1 to 3 integer, R ₁₆Be selected from Ar and NR ₁₇R ₁₈, R wherein ₁₇And R ₁₈Be selected from hydrogen, C independently of one another ₁-C ₅Alkyl and-(CH ₂)-Ar, perhaps R wherein ₁₇And R ₁₈Be joined together to form 5-or 6-unit heterocycle; With

(b) R ₁₃, R ₁₄And R ₁₅Be selected from hydrogen, halogen, C independently of one another ₁-C ₆Alkyl, O-(C ₁-C ₆) alkyl ,-(CH ₂) _e-Ar and-G (CH ₂) _e-Ar, wherein e is 0 to 4 integer; G is selected from O, S and NR ₁₉, R wherein ₁₉Be selected from hydrogen and C ₁-C ₆Alkyl; With

(c) A be selected from-O-and-NH-.

Table 3

Wherein, preferred

(a) R ₁₃And R ₁₅Be independently selected from-OCH ₂-4-pyridine ,-O-propyl group and hydrogen;

(b) R ₁₄Be selected from-OCH ₂-4-pyridine, methyl and hydrogen;

(c) R ₁₂Be selected from-CH ₂-3-pyridine and hydrogen; (c) X is 3,4, the 5-trimethoxyphenyl.

Table 4

Table 5

Other the preferred compound that is used for the inventive method comprises: (a) 3-phenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (b) 3-phenyl-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (c) 3-(3,4, the 5-trimethoxyphenyl)-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (d) 3-(3,4, the 5-trimethoxyphenyl)-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (e) 3-(4, the 5-Dichlorobenzene base)-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (f) 3-(4, the 5-Dichlorobenzene base)-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (g) 3-(4, the 5-methylenedioxyphenyl)-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (h) 3-(4, the 5-methylenedioxyphenyl)-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (i) 3-cyclohexyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (j) 3-cyclohexyl-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (k) (1R)-1,3-diphenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (1) (1R)-1,3-diphenyl-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (m) (1R)-1-cyclohexyl-3-phenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (n) (1R)-1-cyclohexyl-3-phenyl-1-third-2-(E)-thiazolinyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (o) (1R)-1-(4,5-Dichlorobenzene base-3-phenyl)-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-2-pyrrolidine carboxylic acid ester; (p) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-cyclohexyl) ethyl-pyrrolidine 2 carboxylic acid ester; (q) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-cyclohexyl) butyl-pyrrolidine 2 carboxylic acid ester; (r) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-furyl) ethyl-pyrrolidine 2 carboxylic acid ester; (s) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-thienyl) ethyl-pyrrolidine 2 carboxylic acid ester; (t) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-[2-thiazolyl]) ethyl-pyrrolidine 2 carboxylic acid ester; (u) 3-phenyl-1-propyl group (2S)-1-(1,2-dioxy-2-phenyl) ethyl-pyrrolidine 2 carboxylic acid ester; (v) 1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (w) 3-phenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy-4-hydroxybutyl)-pyrrolidine 2 carboxylic acid ester; (x) 3-phenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester; (y) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-Phenylalanine ethyl ester; (z) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-leucine ethyl ester; (aa) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-phenylglycine ethyl ester; (bb) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-Phenylalanine phenylester; (cc) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-Phenylalanine benzyl ester; (dd) 1-[1-(3,3-dimethyl-1,2-dioxy amyl group)-L-proline]-L-isoleucine ethyl ester.

Table 6

B	X
		The 3-phenyl propyl	Phenyl
4-(4-methoxyphenyl) butyl	Phenyl
		The 4-phenyl butyl	Phenyl
4-cyclohexyl butyl	Phenyl
		Benzyl	Methoxyl group
4-cyclohexyl butyl	Methoxyl group
		3-cyclohexyl propyl group	Methoxyl group
3-cyclopenta propyl group	Methoxyl group
		4-cyclohexyl butyl	3,4, the 5-trimethoxyphenyl
The 3-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl butyl	3,4, the 5-trimethoxyphenyl
3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl
		4-(4-methoxyphenyl) butyl	3,4, the 5-trimethoxyphenyl
Benzyl	Phenyl
		Pi-allyl	Phenyl
The 1-naphthyl	Phenyl
		The 2-naphthyl	Phenyl

Benzyl	The 2-methyl-propyl
		Benzyl	The 2-methoxyphenyl
Benzyl	The 3-methoxyphenyl
		Benzyl	The 4-methoxyphenyl
Benzyl	3, the 5-Dimethoxyphenyl
		Benzyl	2, the 6-Dimethoxyphenyl
Benzyl	3,4, the 5-trimethoxyphenyl
		Benzyl	The 4-fluorophenyl
Benzyl	The 3-nitrobenzophenone
		Benzyl	The 4-nitrobenzophenone
Benzyl	The 2-pyridine radicals
		Benzyl	2-pyridine radicals-N-oxide
Benzyl	The 2-furyl
		Benzyl	The 3-indyl
E-3-(4-hydroxy phenyl)-2-methyl-third-2-thiazolinyl	Phenyl
		E-3-phenyl-2-methyl-third-2-thiazolinyl	Phenyl
E-3-[cis-(4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Phenyl
		E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Phenyl
Benzyl	The 2-nitrobenzyl
		Benzyl	The 2-thio-phenyl
Hydrogen	Methoxyl group
		Pi-allyl	Methoxyl group
Benzyl	Methoxyl group
		2-cyclohexyl ethyl	Methoxyl group
3-cyclohexyl propyl group	Methoxyl group
		4-cyclohexyl butyl	Methoxyl group
3-cyclopenta propyl group	Methoxyl group
		E-3-(4-methoxyphenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group
E-3-(3, the 4-Dimethoxyphenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group
		E-3-(4-hydroxy phenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group

E-3-[cis-(4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Methoxyl group
		Benzyl	Cyclohexyl
Benzyl	3, the 4-difluorophenyl
		Benzyl	(E)-2-(4-methoxyphenyl)-vinyl
Benzyl	1-hydroxyl-1-cyclohexyl
		Benzyl	The 2-naphthyl
Benzyl	The 1-naphthyl
		(S)-α-Jia Jibianji	Phenyl
Benzyl	2-hydroxyl-2-THP trtrahydropyranyl
		(R)-α-Jia Jibianji	Phenyl
Benzyl	The 3-trifluoromethyl
		Benzyl	3-benzyl oxygen phenyl
Benzyl	(E)-2-tert-butyl group vinyl
		Benzyl	The 2-trifluoromethyl
4-cyclohexyl butyl	Phenyl
		4-cyclohexyl butyl	3,4, the 5-trimethoxyphenyl
The 4-phenylbenzyl	Phenyl
		The 4-phenylbenzyl	3,4, the 5-trimethoxyphenyl
Benzyl	The 3-ethoxyl phenenyl
		The 3-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
The 3-phenoxy benzyl	Phenyl
		The 4-phenyl butyl	3,4, the 5-trimethoxyphenyl
The 4-phenyl butyl	Phenyl
		Benzyl	3-(3-acrylic oxygen) phenyl
Benzyl	3-(2-propoxyl group) phenyl
		Benzyl	The 1-methyl-propyl
The 2-phenylethyl	Phenyl
		6-phenyl hexyl	Phenyl
The 5-phenylpentyl	3,4, the 5-trimethoxyphenyl
		6-phenyl hexyl	3,4, the 5-trimethoxyphenyl

6-cyclohexyl hexyl	3,4, the 5-trimethoxyphenyl
		The 4-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
5-cyclohexyl amyl group	3,4, the 5-trimethoxyphenyl
		Benzyl	3-(1-butoxy) phenyl
The 4-phenyl butyl	3-(2-propoxyl group) phenyl
		4-(4-iodine substituted phenyl) butyl	3,4, the 5-trimethoxyphenyl
The 4-benzyl iodide	3,4, the 5-trimethoxyphenyl
		2-(2-naphthyl) ethyl	3,4, the 5-trimethoxyphenyl
2-(1-naphthyl) ethyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl butyl	The 4-iodine substituted phenyl
The 4-phenyl butyl	The 3-iodine substituted phenyl
		The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl
		4-(4-methoxyphenyl) butyl	3,4, the 5-trimethoxyphenyl
4-phenyl but-2-ene base	3,4, the 5-trimethoxyphenyl
		4-phenyl but-2-ene base	3,4, the 5-trimethoxyphenyl
4-(4-allyl amino phenyl) propyl group	3,4, the 5-trimethoxyphenyl
		The 4-phenyl propyl	The 1-cyclohexenyl group
4-(4-methoxyphenyl) fourth-3-thiazolinyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl propyl	1-fluoro-1-cyclohexyl
The 4-phenyl propyl	The 3-butoxy phenyl
		3-[3-(N-formyl indole base)] propyl group	3,4, the 5-trimethoxyphenyl
4-(3-indyl) butyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl butyl	Benzyl
The 4-phenyl butyl	The 3-xenyl
		The 4-phenyl butyl	The 4-tert-butyl-phenyl
The 4-phenyl butyl	Cyclohexyl
		The 4-phenyl butyl	Cyclohexyl methyl
The 4-phenyl butyl	3, the 4-methylenedioxyphenyl
		The 4-phenyl butyl	The 4-THP trtrahydropyranyl

The 4-phenyl butyl	3-cyclohexyl-4-methoxyphenyl
		The 4-phenyl butyl	4-(4-methoxy-benzyl oxygen-methyl)-2-furyl
The 4-phenyl butyl	The tert-butyl group
		The 4-phenyl butyl	Ethyl
3-(N-benzimidazolyl) propyl group	3,4, the 5-trimethoxyphenyl
		3-(N-purine radicals) propyl group	3,4, the 5-trimethoxyphenyl
(S, S)-2-methyl-3-hydroxy-4-phenyl propyl group	3,4, the 5-trimethoxyphenyl

Table 7

B	X
		The 3-phenyl propyl	Phenyl
4-(4-methoxyphenyl) butyl	Phenyl
		The 4-phenyl butyl	Phenyl
4-cyclohexyl butyl	Phenyl
		Benzyl	Methoxyl group
4-cyclohexyl butyl	Methoxyl group
		3-cyclohexyl propyl group	Methoxyl group
3-cyclopenta propyl group	Methoxyl group
		4-cyclohexyl butyl	3,4, the 5-trimethoxyphenyl
The 3-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl butyl	3,4, the 5-trimethoxyphenyl
3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl
		4-(4-methoxyphenyl) butyl	3,4, the 5-trimethoxyphenyl
Benzyl	Phenyl
		Pi-allyl	Phenyl
The 1-naphthyl	Phenyl

The 2-naphthyl	Phenyl
		Benzyl	The 2-methyl-propyl
Benzyl	The 2-methoxyphenyl
		Benzyl	The 3-methoxyphenyl
Benzyl	The 4-methoxyphenyl
		Benzyl	3, the 5-Dimethoxyphenyl
Benzyl	2, the 6-Dimethoxyphenyl
		Benzyl	3,4, the 5-trimethoxyphenyl
Benzyl	The 4-fluorophenyl
		Benzyl	The 3-nitrobenzophenone
Benzyl	The 4-nitrobenzophenone
		Benzyl	The 2-pyridine radicals
Benzyl	2-pyridine radicals-N-oxide
		Benzyl	The 2-furyl
Benzyl	The 3-indyl
		E-3-(4-hydroxy phenyl)-2-methyl-third-2-thiazolinyl	Phenyl
E-3-phenyl-2-methyl-third-2-thiazolinyl	Phenyl
		E-3-[cis-(4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Phenyl
E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Phenyl
		Benzyl	The 2-nitrobenzyl
Benzyl	The 2-thio-phenyl
		Hydrogen	Methoxyl group
Pi-allyl	Methoxyl group
		Benzyl	Methoxyl group
2-cyclohexyl ethyl	Methoxyl group
		3-cyclohexyl propyl group	Methoxyl group
4-cyclohexyl butyl	Methoxyl group
		3-cyclopenta propyl group	Methoxyl group
E-3-(4-methoxyphenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group
		E-3-(3, the 4-Dimethoxyphenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group

E-3-(4-hydroxy phenyl)-2-methyl-third-2-thiazolinyl	Methoxyl group
		E-3-[cis-(4-hydroxy-cyclohexyl)]-2-methyl-third-2-thiazolinyl	Methoxyl group
Benzyl	Cyclohexyl
		Benzyl	3, the 4-difluorophenyl
Benzyl	(E)-2-(4-methoxyphenyl)-vinyl
		Benzyl	1-hydroxyl-1-cyclohexyl
Benzyl	The 2-naphthyl
		Benzyl	The 1-naphthyl
(S)-α-Jia Jibianji	Phenyl
		Benzyl	2-hydroxyl-2-THP trtrahydropyranyl
(R)-α-Jia Jibianji	Phenyl
		Benzyl	The 3-trifluoromethyl
Benzyl	3-benzyl oxygen phenyl
		Benzyl	(E)-2-tert-butyl group vinyl
Benzyl	The 2-trifluoromethyl
		4-cyclohexyl butyl	Phenyl
4-cyclohexyl butyl	3,4, the 5-trimethoxyphenyl
		The 4-phenylbenzyl	Phenyl
The 4-phenylbenzyl	3,4, the 5-trimethoxyphenyl
		Benzyl	The 3-ethoxyl phenenyl
The 3-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
		The 3-phenoxy benzyl	Phenyl
The 4-phenyl butyl	3,4, the 5-trimethoxyphenyl
		The 4-phenyl butyl	Phenyl
Benzyl	3-(3-acrylic oxygen) phenyl
		Benzyl	3-(2-propoxyl group) phenyl
Benzyl	The 1-methyl-propyl
		The 2-phenylethyl	Phenyl
6-phenyl hexyl	Phenyl
		The 5-phenylpentyl	3,4, the 5-trimethoxyphenyl

6-phenyl hexyl	3,4, the 5-trimethoxyphenyl
		6-cyclohexyl hexyl	3,4, the 5-trimethoxyphenyl
The 4-phenoxy benzyl	3,4, the 5-trimethoxyphenyl
		5-cyclohexyl amyl group	3,4, the 5-trimethoxyphenyl
Benzyl	3-(1-butoxy) phenyl
		The 4-phenyl butyl	3-(2-propoxyl group) phenyl
4-(4-iodine substituted phenyl) butyl	3,4, the 5-trimethoxyphenyl
		The 4-benzyl iodide	3,4, the 5-trimethoxyphenyl
2-(2-naphthyl) ethyl	3,4, the 5-trimethoxyphenyl
		2-(1-naphthyl) ethyl	3,4, the 5-trimethoxyphenyl
The 4-phenyl butyl	The 4-iodine substituted phenyl
		The 4-phenyl butyl	The 3-iodine substituted phenyl
The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
		3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl
4-(4-methoxyphenyl) butyl	3,4, the 5-trimethoxyphenyl
		4-phenyl but-2-ene base	3,4, the 5-trimethoxyphenyl
4-phenyl fourth-3-thiazolinyl	3,4, the 5-trimethoxyphenyl
		4-(4-allyl amino phenyl) propyl group	3,4, the 5-trimethoxyphenyl
The 4-phenyl propyl	The 1-cyclohexenyl group
		4-(4-methoxyphenyl) fourth-3-thiazolinyl	3,4, the 5-trimethoxyphenyl
The 4-phenyl propyl	1-fluoro-1-cyclohexyl
		The 4-phenyl propyl	The 3-butoxy phenyl
3-[3-(N-formyl indole base)] propyl group	3,4, the 5-trimethoxyphenyl
		4-(3-indyl) butyl	3,4, the 5-trimethoxyphenyl
The 4-phenyl butyl	Benzyl
		The 4-phenyl butyl	The 3-xenyl
The 4-phenyl butyl	The 4-tert-butyl-phenyl
		The 4-phenyl butyl	Cyclohexyl
The 4-phenyl butyl	Cyclohexyl methyl
		The 4-phenyl butyl	3, the 4-methylenedioxyphenyl

The 4-phenyl butyl	The 4-THP trtrahydropyranyl
		The 4-phenyl butyl	3-cyclohexyl-4-methoxyphenyl
The 4-phenyl butyl	4-(4-methoxy-benzyl oxygen-methyl)-2-furyl
		The 4-phenyl butyl	The tert-butyl group
The 4-phenyl butyl	Ethyl
		3-(N-benzimidazolyl) propyl group	3,4, the 5-trimethoxyphenyl
3-(N-purine radicals) propyl group	3,4, the 5-trimethoxyphenyl
		(S, S)-2-methyl-3-hydroxy-4-phenyl propyl group	3,4, the 5-trimethoxyphenyl

Table 8

B	D	X
			The 3-phenyl propyl	3-(3-pyridine radicals) propyl group	Phenyl
The 3-phenyl propyl	3-(2-pyridine radicals) propyl group	Phenyl
			The 3-phenyl propyl	2-(4-methoxyphenyl) ethyl	Phenyl
The 3-phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	2-(3-pyridine radicals)	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(2-pyridine radicals)	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	3-(4-methoxyphenyl) propyl group	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(3-pyridine radicals) propyl group	The 3-isopropyl phenyl
3-(pyridine-2-yl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 3-Phenoxyphenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Phenyl	The 3-Phenoxyphenyl	3,4, the 5-trimethoxyphenyl
			Phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-(pyridin-3-yl) ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl

E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-second-2-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Benzyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Benzyl	3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl
			The 2-phenylethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-(4-methoxyphenyl) ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			2-(4-methoxyphenyl) ethyl	The 3-phenyl propyl	Phenyl
3-(N-benzimidazolyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Benzyl	The 2-phenylethyl	3,4, the 5-trimethoxyphenyl
3-(4-methoxyphenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(N-(7-azaindolyl)-propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(N-purine radicals) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(4-hydroxymethyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	3-benzyl oxygen base phenyl
			3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	3-pi-allyl oxygen base phenyl
3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	The 3-isopropyl phenyl
			3-(thiophene-2-yl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(4-carboxyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl butyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-hydroxymethyl phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			2-pi-allyl oxygen phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(3-hydroxymethyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(3-carboxyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-hydroxymethyl phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 2-hydroxy phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Pyridin-3-yl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(thiophene-2-yl) propyl group	The 4-phenyl propyl	3,4, the 5-trimethoxyphenyl
The 5-phenylpentyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-pi-allyl oxygen base propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(N, N-dimethylamino carbonyl) benzene	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl

Base] propyl group
			3-[4-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
4-pi-allyl oxygen Ji Dingji	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-pi-allyl oxygen base third-1-alkynyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(piperidines-1-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			5-pi-allyl oxygen base nonyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Methyl	3, two (benzyl oxygen) phenyl of 5-	3,4, the 5-trimethoxyphenyl
			2-pi-allyl oxygen ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen-(E)-third-1-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[3-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The last of the ten Heavenly stems-the 9-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(thiomorpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(morpholine-4-carbonyl) phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(1-methyl piperazine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(1-benzyl diethylenediamine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[3-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N-pyridine-2-base amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Pyridin-3-yl	3-(pyridin-3-yl) propyl group	3,4, the 5-trimethoxyphenyl
			Third-2-thiazolinyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
Pyridin-3-yl	3-(pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
			Methyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	2,3,4-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(morpholine-4-carbonyl)-4-(pyridin-4-yl first	3,4, the 5-trimethoxyphenyl

	The oxygen base) phenyl
			Methyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			Methyl	3, two (pyridin-4-yl methoxyl group) phenyl of 5-	3,4, the 5-trimethoxyphenyl
Ethyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			Methyl	3,4,5-three (pyrazine-2-ylmethoxy) phenyl	3,4, the 5-trimethoxyphenyl
Vinyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			3-pi-allyl oxygen propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(N, N-dimethyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
4-pi-allyl oxygen-butyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-pi-allyl oxygen third-1-alkynyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(piperidines-1-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			5-pi-allyl oxygen nonyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Methyl	3, two (benzyl oxygen) phenyl of 5-	3,4, the 5-trimethoxyphenyl
			2-pi-allyl oxygen ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen-(E)-third-1-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[3-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The last of the ten Heavenly stems-the 9-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(thiomorpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(morpholine-4-carbonyl) phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(1-methyl piperazine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(1-benzyl diethylenediamine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[3-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Propyl group	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl

2-isopropoxy-3, two (pyridin-4-yl methoxyl group) phenyl of 4-	Methyl	3,4, the 5-trimethoxyphenyl
			Benzyl oxygen methyl	Benzyl oxygen phenyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	Phenyl	3-benzyl oxygen-4-methoxyphenyl

Table 9

B	D	X
			The 3-phenyl propyl	3-(3-pyridine radicals) propyl group	Phenyl
The 3-phenyl propyl	3-(2-pyridine radicals) propyl group	Phenyl
			The 3-phenyl propyl	2-(4-methoxyphenyl) ethyl	Phenyl
The 3-phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	2-(3-pyridine radicals)	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(2-pyridine radicals)	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	3-(4-methoxyphenyl) propyl group	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(3-pyridine radicals) propyl group	The 3-isopropyl phenyl
3-(pyridine-2-yl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 3-Phenoxyphenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Phenyl	The 3-Phenoxyphenyl	3,4, the 5-trimethoxyphenyl
			Phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-(pyridin-3-yl) ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			E-3-[is trans-and (4-hydroxy-cyclohexyl)]-2-methyl-second-2-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Benzyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Benzyl	3-(3-indyl) propyl group	3,4, the 5-trimethoxyphenyl

The 2-phenylethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			2-(4-methoxyphenyl) ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-(4-methoxyphenyl) ethyl	The 3-phenyl propyl	Phenyl
			3-(N-benzimidazolyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Benzyl	The 2-phenylethyl	3,4, the 5-trimethoxyphenyl
			3-(4-methoxyphenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(N-(7-azaindolyl)-propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(N-purine radicals) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(4-hydroxymethyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	3-benzyl oxygen base phenyl
3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	3-pi-allyl oxygen base phenyl
			3-(pyridin-3-yl) propyl group	The 3-phenyl propyl	The 3-isopropyl phenyl
3-(thiophene-2-yl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(4-carboxyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl butyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			2-hydroxymethyl phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
2-pi-allyl oxygen phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(3-hydroxymethyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(3-carboxyl phenyl) propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-hydroxymethyl phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The 2-hydroxy phenyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Pyridin-3-yl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(thiophene-2-yl) propyl group	The 4-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The 5-phenylpentyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen base propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N, N-dimethylamino carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			4-pi-allyl oxygen Ji Dingji	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen base third-1-alkynyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl

3-[4-(piperidines-1-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			5-pi-allyl oxygen base nonyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Methyl	3, two (benzyl oxygen) phenyl of 5-	3,4, the 5-trimethoxyphenyl
			2-pi-allyl oxygen ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen-(E)-third-1-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[3-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
The last of the ten Heavenly stems-the 9-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(thiomorpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-(morpholine-4-carbonyl) phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(1-methyl piperazine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(1-benzyl diethylenediamine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[3-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N-pyridine-2-base amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Pyridin-3-yl	3-(pyridin-3-yl) propyl group	3,4, the 5-trimethoxyphenyl
			Third-2-thiazolinyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
Pyridin-3-yl	3-(pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
			Methyl	3, two (pyridin-4-yl methoxyl group) phenyl of 4-	3,4, the 5-trimethoxyphenyl
The 3-phenyl propyl	2,3,4-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	3-(morpholine-4-carbonyl)-4-(pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
Methyl	3,4,5-three (pyridin-4-yl methoxy	3,4, the 5-trimethoxyphenyl

	Base) phenyl
			The 3-phenyl propyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
Methyl	3, two (pyridin-4-yl methoxyl group) phenyl of 5-	3,4, the 5-trimethoxyphenyl
			Ethyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
Methyl	3,4,5-three (pyrazine-2-ylmethoxy) phenyl	3,4, the 5-trimethoxyphenyl
			Vinyl	3,4,5-three (pyridin-4-yl methoxyl group) phenyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(N, N-dimethyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			4-pi-allyl oxygen-butyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-pi-allyl oxygen third-1-alkynyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(piperidines-1-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
5-pi-allyl oxygen nonyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			Methyl	3, two (benzyl oxygen) phenyl of 5-	3,4, the 5-trimethoxyphenyl
2-pi-allyl oxygen ethyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-pi-allyl oxygen-(E)-third-1-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[3-(morpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			The last of the ten Heavenly stems-the 9-thiazolinyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(thiomorpholine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-(morpholine-4-carbonyl) phenyl propyl	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[4-(1-methyl piperazine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
3-[4-(1-benzyl diethylenediamine-4-carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
			3-[3-(N-benzyl amine carbonyl) phenyl] propyl group	The 3-phenyl propyl	3,4, the 5-trimethoxyphenyl
Propyl group	3,4,5-three (pyridin-4-yl methoxy	3,4, the 5-trimethoxyphenyl

	Base) phenyl
			2-isopropoxy-3, two (pyridin-4-yl methoxyl group) phenyl of 4-	Methyl	3,4, the 5-trimethoxyphenyl
Benzyl oxygen methyl	Benzyl oxygen phenyl	3,4, the 5-trimethoxyphenyl
			The 3-phenyl propyl	Phenyl	3-benzyl oxygen-4-methoxyphenyl

Table 10

Table 12

Table 13

Table 14

????B	????X
		Benzyl	Phenyl
The tert-butyl group	The 2-furyl

The tert-butyl group	Methoxyl group
		Benzyl	Ethyl
Benzyl	The 3-methoxyphenyl
		Benzyl	The 2-pyridine radicals

Table 15

????B	????X
		Benzyl	Phenyl
The tert-butyl group	The 2-furyl
		The tert-butyl group	Methoxyl group
Benzyl	Ethyl
		Benzyl	The 3-methoxyphenyl
Benzyl	The 2-pyridine radicals

Analytical method

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

Telogen transition detection

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

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

Use the C3H mouse in three groups of 44 day ages: media (vehicle) matched group, positive controls and test compounds group, what wherein the test compounds group was given clothes is the chemical compound that is used for the inventive method.Detection period was at least 19 days, and 15 treatments day (wherein treatment day is Mon-Fri) are wherein arranged.First day is first day of treatment.Most of researchs will finish at the 19th day, if but melanogen generates response looks to be positive but when carrying out slowly, some researchs will proceed to the 24th day so.Typical research design has been shown in the following table 16:

Table 16

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

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

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

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

Table 17

Visual observations result	Rank
		Shallow white skin color	????0
Skin is light grey (beginning the anagen of expression)	????1
		Blue spot appears	????2
The blue spot accumulation forms a BigBlue zone	????3

Skin is black and blue color (almost being black), and the major part of area for treatment is covered (expression mice anagen phase) completely by color

???4

Immunosuppressant detects

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

Dead (the CO of the peace in from 7 to 16 ages in week ₂Suffocate) bull C3H mouse (mice that lives can be from Harlan Sprague Dawley, Inc., Indianapolis, IN has bought) excision spleen.With spleen be placed on immediately cold Hanks Balanced Salt Solution (HBSS, available from Gibco-BRL, Gaithersburg, MD) in.Then, spleen is ground between freezing glass slide, and filter to remove fragment of tissue by aseptic screen cloth.With the cell suspending liquid of gained be placed on isopyknic Ficoll-Paque Plus (available from Pharmacia Biotech, Piscataway, NJ) following and under 400 * g 20 ℃ centrifugal about 40 minutes to collect splenocyte.Use disposable pipet from collecting splenocyte at the interface, and use the HBSS washed twice, then under 100 * g 20 ℃ centrifugal 10 minutes down.Splenocyte is resuspended in 5 to the 10 ml cells culture medium, this cell culture medium constitutes (cell culture medium of having bought from Gibco-BRL) by the red RPMI1640 of reactive phenol, and it contains 10% heat-inactivated hyclone (Gibco-BRL), penicillin (50U/ml), streptomycin (100 mcg/ml), L-glutaminate (2mM), 2 mercapto ethanol (10 ^-5M) and N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) (10mM).Use and count and check its viability as the trypan blue pair cell.With splenocyte with 10 ⁶Cells/ml is resuspended in the culture medium and with 10 ⁵Cells/well moves in the round bottom plate in 96 holes.By adding 50 microlitres/hole concanavalin A (conconavalinA) (final detectable concentration is 5 mcg/ml) splenocyte is activated in the existence of test compounds or not.Test compounds is formed in stock solution in the dimethyl sulfoxide (DMSO), and dilution and add with 50 microlitres/hole in culture medium then makes the ultimate density that detects DMSO in the liquid be lower than 0.05%.At 37 ℃ at 5%CO ₂Down plate was cultivated 48 hours.After 48 hours, with cell with the methyl in 1 μ Ci/ hole- ³(available from Amersham, Buckinghamshire England) adds pulse and also cultivated 24 hours again the H-thymidine.

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

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

Preparation method

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

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

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

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

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

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

This paper uses following abbreviation:

Reagent	Abbreviation
		N, dinethylformamide	DMF
The I-hydroxybenzotriazole hydrate	HOBt
		Tert-butoxycarbonyl	BOC
(benzotriazole-1-base oxygen) tripyrrole alkyl phosphorus hexafluorophosphate is (available from Fluka Chemical, Switzerland)	PyBOP
		Oxolane	THF
N, the N-diisopropyl ethyl amine	i-Pr 2NEt or i-Pr 2EtN
		Trifluoroacetic acid	TFA

Embodiment 1

Above-claimed cpd is that this license now transfers Guilford Pharmaceuticals Inc. on March 25th, 1997 according to people's such as Hamilton US 5,614,547 described preparations.

Embodiment 2

Above-claimed cpd is that this license now transfers Guilford Pharmaceuticals Inc. on March 25th, 1997 according to people's such as Hamilton US 5,614,547 described preparations.

Embodiment 3

3a. (S)-and (N-tertbutyloxycarbonyl)-pipecolinic acid 1,7-diphenyl-4-heptyl amide: (S)-(N-tertbutyloxycarbonyl)-pipecolinic acid (4.7 grams, 20.3 mMs) is dissolved among 200 milliliters of DMF.Add 1, amino heptane of 7-diphenyl-4-(5.44 grams, 20.3 mMs) (preparing) and i-Pr according to following embodiment 4 ₂EtN (7.1 milliliters, 40.7 mMs) next adds PyBOP (10.6 grams, 20.3 mMs).At room temperature reaction stirred is 18 hours, pours into then in the ice-cold 0.1N hydrochloric acid (600 milliliters), extracts with ethyl acetate (800 milliliters).Separate each layer, organic layer is with saline (200 milliliters), saturated sodium bicarbonate solution (400 milliliters) and saline (200 milliliters) continuous washing.With the organic solution dried over mgso, filter vacuum concentration.With purifying products, obtain required amide 3a by silica gel chromatography.

3b. (S)-and pipecolinic acid 1,7-diphenyl-4-heptyl amide: amide 3a (8.74 grams, 18.3 mMs) is dissolved in 150 milliliters of anhydrous methylene chlorides.In 5 minutes, dropwise add TFA (100 milliliters).After two hours, cooling mixture in ice bath adds the unsaturated carbonate potassium solution and is approximately till 8 until pH.Mixture is transferred in the separatory funnel that comprises dichloromethane (200 milliliters) and water (200 milliliters), rocks.With before the dried over mgso, separate organic layer and water (200 milliliters) washing organic layer.Filtering mixt, vacuum concentration obtain required amide 3b.

3c. (S)-and N-(3 ', 4 ', 5 '-trimethoxyphenyl is glyoxyl-based)-pipecolinic acid 1,7-diphenyl-4-heptyl amide: at room temperature, amide 3b (0.65 gram, 1.72 mMs) is dissolved in 35 milliliters of dry DMF.Add 3 ', 4 ', 5 '-methoxyphenyl glyoxalic acid (0.4 gram, 1.72 mMs) and i-Pr ₂EtN (0.44 gram, 3.43 mMs) next adds PyBOP (0.9 gram, 1.72 mMs).At room temperature stirred reaction mixture is 21 hours, pours into then in the ice-cold 0.1N hydrochloric acid (150 milliliters), and extracts with ethyl acetate (150 milliliters).Separate each layer, organic layer washs with saline (50 milliliters), saturated sodium bicarbonate solution (150 milliliters) and saline (50 milliliters) order.The organic solution dried over mgso is filtered vacuum concentration.By the chromatogram purification crude product on silica gel, obtain required amide 3c.

Embodiment 4

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

4b.1, the amino heptane of 7-diphenyl-4-: use the reactant mixture of charging hopper with methanol (3.2 liters) dilution 4a.Add sodium borohydride (83.4 grams, 2.2 moles) several times.After reinforced finishing, reactant was at room temperature stirred 6 hours.Make the reactant mixture quenching 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) that water layer is extracted twice.With sodium chloride solution with the ether extract washing that merges once, drying is filtered and is carried out vacuum concentration, obtains thick product.This product is diluted in the ether (1.2 liters), and by slowly adding 1M hydrochloric acid (1.2 liters) acidify.Mixture was stirred 1 hour vacuum concentration.The precipitate dilution in acetonitrile of gained, and restir 16 hours.Filter to collect required 1, the amino heptane of 7-diphenyl-4-.

Embodiment 5

Above-claimed cpd is that this license now transfers Vertex Pharmaceuticals Inc. on April 15th, 1997 according to people's such as Armistead US 5,620,971 described preparations.

Embodiment 6

Above-claimed cpd is that this license now transfers Vertex Pharmaceuticals Inc. on April 15th, 1997 according to people's such as Armistead US 5,620,971 described preparations.

Embodiment 7

Above-claimed cpd is that this license now transfers Vertex Pharmaceuticals Inc. on April 15th, 1997 according to people's such as Armistead US 5,620,971 described preparations.

Embodiment 8

Above-claimed cpd is that this license now transfers Vertex Pharmaceuticals Inc. on March 10th, 1998 according to people's such as Zelle US 5,726,184 described preparations.

The purposes of The compounds of this invention

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

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

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

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

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

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

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

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

Can unite the selection of pharmaceutical carrier of use basically by the decision of the route of administration of chemical compound with chemical compound of the present invention.

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

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

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

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

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

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

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

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

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

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

Chemical compound of the present invention also can be with the form administration of liposome transfer system, as the form administration of small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be formed as cholesterol, stearylamine or phosphatidylcholine by various phospholipid.The local liposome of describing in used preferred formulation use of chemical compound of the present invention as the following file that transmits: people such as Dowton, " the liposome component transmits the influence of the cyclosporin A of encapsulate: 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, US 4,911,928, transfer Micro-Pak, Inc., authorize March 27 nineteen ninety.

Chemical compound of the present invention also can pass through ionotherapy (iontophoresis) administration.Referring to; As, www.unipr.it/arpa/dipfarm/erasmus/erasm 14.html, people such as Banga, " the iontophoretic treatment transporter that is used for percutaneous transmission peptide/pharmaceutical grade protein " Pharm.Res. based on hydrogel, 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, " the modern ionotherapy that is used for topical remedy's transmission " Int.J.Pharm, the 123rd volume, 159-171 (1995), people such as Green, " transmit a series of tripeptides " through the outer ionotherapy of skin volume, Pharm.Res., the 8th volume, 1121-1127 page or leaf (1991), people such as Jadoul, " fentanyl (Fentanyl) that transmits by the ionotherapy in the skin and TRH quantitatively and locate ", Int.J.Pharm., the 120th volume, 221-8 (1995), people such as O ' Brien, " its antiviral activity; the up-to-date summary of pharmacokinetics performance and therapeutic efficiency ", Drugs, the 37th volume, 233-309 page or leaf (1989), people such as Parry, " bioavaliability of acyclovir in the human body skin ", J.Invest.Dermatol., the the 98th (6), 856-63 (1992), people such as Santi, " medicine of salmon calcitonin storage source composition and transmission in the percutaneous ionotherapy ", Pharm.Res., the 14th (1) volume, 63-66 page or leaf (1997), people such as Santi, " the counter ion electric osmose therapy-mobile parameter of decision electric osmose: I.pH and ionic strength ", J.Control.Release, the 38th volume, 159-165 page or leaf (1996), people such as Santi, " the counter ion electric osmose therapy-mobile parameter of decision electric osmose: the II. electrode chamber is formed ", J.Control.Release, the 42nd volume, 29-36 page or leaf (1996), people such as Rao, " non-infringement glucose monitoring in counter ion electric osmose therapy-human body ", Pharm.Res., the 12nd (12) volume, 1869-1873 page or leaf (1995), people such as Thysman, " in rat, transmit human calcitonin ", J.Pharm.Pharmacol., the 46th volume by ionotherapy, 725-730 page or leaf (1994), people such as Volpato, " strengthening the transmission of acyclovir ", Pharm.Res. through nude mice skin by electricity repulsion and electric osmose ionotherapy, the the 12nd (11) volume, 1623-1627 page or leaf (1995).

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

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

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

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

Another kind of suitable optional hair growth stimulant is that immunosuppressant or non-immunosuppressant are as 1) cyclosporin and cyclosporin analog, comprise those that describe in the following files: the temporary transient patent application serial number 60/122 of the U.S., 925, people such as Fulmer, on March 5th, 1999 submitted to, introduce the present invention as a reference, with 2) the FK506 analog, those as describing in the following file: the temporary transient number of patent application 60/147,279 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,313 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,280 of the U.S., people such as Degenhardt, on August 5th, 1999 submitted to; The temporary transient number of patent application 60/147,278 of the U.S., people such as 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 antibacterial, as selenium sulfide, ketoconazole, triclocarban (triclocarbon), Triclosan (triclosan), 2-mercaptopyridine zinc oxide (zinc pyrithione), itraconazole (itraconazole), asiatic acid (asiatic acid), hinokitiol, mipirocin and EPA 0,680, those that describe in 745 (introducing the present invention as a reference), clinacycin hydrochlorate, benzoyl peroxide, benzyl peroxide and minocycline (minocyclin).

The antibiotic medicine also can be used as optional hair growth stimulant and adds in the compositions of the present invention.The example of suitable antibiotic medicine can comprise glucocorticoid such as hydrocortisone, momestasone furoate and meticortelone, non-steroidal anti-inflammatory drug comprises cyclooxygenase or lipoxidase inhibitor, as U.S. Pat 5,756, those that describe in 092, and those chemical compounds of describing in benzydamine (benzydamine), salicylic acid and the following files: EPA 0,770,399 (on May 2nd, 1997 is open); WO 94/06434 (on March 31st, 1994 is open) and FR 2,268,523 (on November 27th, 1975 is open) introduce the present invention as a reference with all these files.

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

Prostaglandin agonists or antagonist also can be as the optional hair growth stimulant in the present composition.The suitable prostaglandin agonists or the example of antagonist comprise those that describe in latanoprost and the following files: WO 98/33497, Johnstone, and on August 6th, 1998 is open; WO 95/11003, Stjernschantz, and April 27 nineteen ninety-five is open; JP 97-100091 (Ueno) and JP 96-134242 (Nakamura).

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

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

The optional hair growth stimulant that is used for other type of the present invention comprises class flavin (flavinoids), ascomycin derivative and analog, histamine antagonist example hydrochloric acid diphenhydramine, other triterpenes such as oleanolic acid (oleanolic acid) and ursolic acid (ursolic acid), as describing in the following file those: US 5,529,769, JP 10017431, WO 95/35103, US 5,468,888, JP09067253, WO 92/09262, JP 62093215, US 5,631,282, US 5,679,705, JP08193094, angle glycoside (saponins), as EP 0,558,509 (people such as Bonte), open and the WO 97/01346 of JIUYUE in 1993 8 days people such as () Bonte, those that describe on January 6th, 1997 open (these two files are introduced the present invention as a reference), Dan Baijutang enzyme or glycosaminoglycans enzyme inhibitor such as US5,015,470, on May 14th, 1991 authorized, US 5,300, on April 5th, 284,1994 authorized and US 5,185,325, authorized (these patents are introduced the present invention as a reference) on February 9th, 1993, estrogen agonist and antagonist, pseudoterins, cytokine and somatomedin promoter, analog or inhibitor such as interleukin-1 inhibitor, interleukin-6 inhibitor, interleukin 10 promoter and tumor necrosis factor inhibitors, vitamin such as novel vitamin D analogues and pth antagonist, vitamin B12 analog and pantothenylol, interfuron agonist and antagonist, hydroxy acid such as USP5,550, described in 158 those, benzophenone and hydantoin anticonvulsant such as phenytoin (phenytoin).

Other additional hair growth stimulant is described in detail in the following files: JP 09-157, and 139, people such as Tsuji, on June 17th, 1997 is open; EP 0277455 A1, Mirabeau, on August 10th, 1988 is open; WO 97/05887, people such as Cabo Soler, and on February 20th, 1997 is open; WO92/16186, people such as Bonte, on March 13rd, 1992 is open; JP 62-93215, people such as Okazaki, on April 28th, 1987 is open; US 4,987,150, people such as Kurono, and on January 22nd, 1991 authorized; JP 290811, people such as Ohba, and on October 15th, 1992 is open; JP 05-286,835, people such as Tanaka, on November 2nd, 1993 is open; FR 2,723,313, Greff, and on August 2nd, 1994 is open; US 5,015,470, people such as GibSon, and on May 14th, 1991 authorized; US 5,559, and JIUYUE was authorized on the 24th in 092,1996 year; US 5,536, and on July 16th, 751,1996 authorized; US 5,714, and on February 3rd, 515,1998 authorized; EPA 0,319, and on June 14th, 991,1989 is open; EPA 0,357, and on October 6th, 630,1988 is open; EPA 0,573, and December disclosed on the 8th in 253,1993 years; JP 61-260010, on November 18th, 1986 is open; US 5,772, and on June 30th, 990,1998 authorized; US 5,053, and on October 1st, 410,1991 authorized; US 4,761, and on August 2nd, 401,1988 authorized; All above-mentioned files are introduced the present invention as a reference.

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

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

The embodiment of compositions administration

The following example is not intended to limit the invention, but for the explanation of implementing method of the present invention is provided to those of ordinary skill.In each embodiment, be different from the chemical compound replacement that the chemical compound outside the chemical compound of being mentioned can be had structure described herein in an embodiment, have similar result.

Embodiment A

Preparation is used for topical drug delivery composition, comprises:

Component	Consumption
		The chemical compound of embodiment 3	5％
Ethanol	57％
		Propylene glycol	19％
Different sorbic acid dimethyl ester (dimethyl isosorbide)	19％

The male patient who suffers from men's style bald head treats with method of the present invention.Concrete scheme is the local above-mentioned composition that uses every day, continues for 6 weeks.

Embodiment B

" 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 " according to people such as Dowton, S.T.P. Pharma Sciences, the 3rd volume, 404-407 page or leaf (1993) is described, uses the chemical compound of embodiment 2 to replace cyclosporin A and use Novasome 1 to form as the nonionic liposome preparing the topical drug delivery composition according to the present invention.

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

Embodiment C

The preparation shampoo comprises:

Component	Embodiment C-1	Embodiment C-2	Embodiment C-3	Embodiment C-4
					Ammonium lauryl sulfate	????11.5％	????11.5％	????9.5％	????7.5％
Lauryl polyethenoxy ether sodium sulfate	????4％	????3％	????2％	????2％
					Coconut monoethanol amide	????2％	????2％	????2％	????2％
Glycol distearate	????2％	????2％	????2％	????2％
					Spermol	????2％	????2％	????2％	????2％
Stearyl alcohol	????1.2％	????1.2％	????1.2％	????1.2％
					Glycerol	????1％	????1％	????1％	????1％
Polyquaternium?10	????0.5％	????0.25％	????-	????-
					Polyquaternium?24	????-	????-	????0.5％	????0.25％
Sodium chloride	????0.1％	????0.1％	????0.1％	????0.1％
					The Olestra of Cotton Gossypii acid fatty acid	????3％	????3％	????-	????-
The Olestra of behenic acid fatty acid	????2％	????3％	????-	????-
					Polydimethylsiloxane	????-	????-	????3％	????2％
Cocos nucifera oil aminopropyl betanin	????-	????1％	????3％	????3％
					Lauryl dimethyl amine oxide	????1.5％	????1.5％	????1.5％	????1.5％
The decyl polydextrose	????-	????-	????1％	????1％
					DMDM Hydantoin	????0.15％	????0.15％	????0.15％	????0.15％
The chemical compound of embodiment 5	????2％	????-	????-	????-
					The chemical compound of embodiment 1	????-	????5％	????-	????-
The chemical compound of embodiment 7	????-	????-	????3％	????-
					The chemical compound of embodiment 8	????-	????-	????-	????6％
Phenyl phenol	????0.5％	????0.5％	????0.5％	????0.5％

Spice	????0.5％	????0.5％	????0.5％	????0.5％
					Water	In right amount	In right amount	In right amount	In right amount

The male patient who suffers from men's style bald head treats with method of the present invention.Concrete scheme is local the use above-mentioned shampoo, lasting 12 weeks every day.

Claims (10)

1. treat the method for alopecia, comprise that described compositions comprises: the chemical compound that (a) has the non-inhibity of following structure to a kind of compositions of clothes:

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

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

(ii) A is selected from CH ₂, O and NR ₁

(iii) R ₁Be selected from hydrogen and alkyl;

(iv) J is selected from hydrogen, C ₁-C ₆Alkyl, C ₃-C ₆The C that alkenyl, benzyl, Ar replace ₁-C ₆Alkyl,

The C that Ar replaces ₃-C ₆The C that alkenyl, Ar replace ₃-C ₆Alkynyl; K is selected from C ₁-C ₆Alkane

The C that base, Ar replace ₁-C ₆The C that alkyl, Ar replace ₂-C ₆Alkenyl, Ar replace

C ₂-C ₆Alkynyl and cyclohexyl methyl; Perhaps J and K can be joined together to form 5-, 6-

Or 7-unit heterocycle, wherein this ring can randomly comprise be selected from other following hetero atoms: O,

S, S (O), S (O) ₂, NH and NE, wherein be joined together to form replacement as B and D

Or during unsubstituted tetrahydronaphthalene part, J and K can randomly be joined together to form 5-

Or 6-unit and the condensed carbocyclic ring of phenyl ring;

(v) X is selected from hydrogen, C ₁-C ₉Alkyl, C ₂-C ₉Alkenyl, C ₅-C ₇Cycloalkyl, C ₅-C ₇Cyclenes

Base, Ar ,-OR ₂, [C ₁-C ₄Alkyl]-Y, [C ₂-C ₄Alkenyl]-Y, Y and-NR ₃R ₄

(vi) R ₂, R ₃, R ₄, B, D and E be selected from zero independently of one another, hydrogen, Ar, C ₁-C ₆Alkyl,

C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Alkyl, C ₅-C ₇

The C of cycloalkyl substituted ₃-C ₆Alkenyl, C ₅-C ₇The C of cycloalkyl substituted ₃-C ₆Alkynyl, C ₅-C ₇

The C that cycloalkenyl group replaces ₁-C ₆Alkyl, C ₅-C ₇The C that cycloalkenyl group replaces ₃-C ₆Alkenyl, C ₅-C ₇

The C that cycloalkenyl group replaces ₃-C ₆The C that alkynyl, Ar replace ₁-C ₆The C that alkyl, Ar replace ₃-

C ₆The C that alkenyl, Ar replace ₃-C ₆Alkynyl; Wherein in alkyl, alkenyl and the alkynyl

One or more CH ₂Part can randomly be selected from following hetero atom and be replaced: O, S,

S (O), S (O) ₂And NR, wherein R is selected from hydrogen, C ₁-C ₄Alkyl, C ₃-C ₄Alkenyl,

C ₃-C ₄Alkynyl and C ₁-C ₄The bridge joint alkyl, its jackshaft is at the N of NR and contain heteroatomic alkane

Form between the carbon atom in base, alkenyl or the alkynyl with the formation bridged ring, and wherein the bridge joint ring randomly condenses with Ar; Wherein B and D can also be joined together to form 5-, 6-or 7-unit carbocyclic ring, and this encircles randomly with aryl-condensed; Wherein B and D can also be independently of one another: Wherein Z is selected from hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl and C ₂-C ₆Alkynyl; V is selected from 5-, the 6-of Ar and replacement or 7-unit carbocyclic ring, and it has and is independently selected from following substituent group: oxo, hydrogen, hydroxyl, O-(C ₁-C ₄Alkyl) and O-(C ₂-C ₄Alkenyl); Wherein B also can be T, shows structure under wherein T has:

X wherein ₂Be selected from O and NR ₁₀, R wherein ₁₀Be selected from hydrogen, C ₁-C ₆Alkyl and C ₁-C ₆Chain

Thiazolinyl; R ₉Be selected from phenyl, benzyl, C ₁-C ₅Alkyl, C ₁-C ₅Alkenyl, phenyl replace

C ₁-C ₅The C that alkyl, phenyl replace ₁-C ₅Alkenyl; Wherein when B is T, that

D is R ₈, R wherein ₈Be selected from randomly by C ₁-C ₈The C of cycloalkyl substituted ₁-C ₈Alkyl,

And Ar; And R wherein ₃And R ₄Also can connect together and form 5-, 6-or 7-unit heterolipid

Family or aromatic ring; (vii) Ar and Y are selected from phenyl, benzyl, 1-naphthyl, 2-naphthyl, indenyl, azulene independently of one another

Base, fluorenyl, anthryl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-

Pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals,

Pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, different triazolyl, 1,2,3-

Oxadiazole base, 1,2,3-triazoles base, 1,3,4-thiadiazolyl group, pyridazinyl, pyrimidine radicals,

Pyrazinyl, 1,3,5-triazines base, trithiane base, indolizine base, indyl, different Yin

Diindyl base, 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thio phenyl

Base, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, 4H-quinolizinyl,

Quinolyl, 1,2,3,4-tetrahydric quinoline group, isoquinolyl, 1,2,3, the 4-tetrahydrochysene is different

Quinolyl, cinnolinyl, 2 base, quinazolyl, quinoxalinyl, 1,8-

Phthalazinyl, pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, fen

Oxazinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, dioxane between 3-

Pentenyl, imidazolidinyl, 2H-pyranose, 4H-pyranose, piperidyl, 1,4-Er Evil

Alkyl, morpholinyl, 1,4-dithiane base, thio-morpholinyl, piperazinyl, quininuclidinyl;

Wherein have one or more following substituent groups that are independently selected from the Ar: hydrogen, halogen,

Hydroxyl, nitro ,-SO ₃H, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Alkyl, C ₂-C ₆

Alkenyl, O-(C ₁-C ₆Alkyl), O-(C ₂-C ₄Alkenyl), O-benzyl, O-phenyl, 1,

The 2-methylene-dioxy ,-NR ₅R ₆, carboxyl, N-(C ₁-C ₅Alkyl) Methanamide, N-(C ₃-C ₅

Alkenyl) Methanamide, N, N-two-(C ₁-C ₅Alkyl) Methanamide, N, N-two-(C ₃-C ₅

Alkenyl) Methanamide, N-morpholino Methanamide, N-benzyl carboxylic acid amides, N-thiomorpholine generation

Carboxylic acid amides, N-pyridine formoxyl carboxylic acid amides, morpholinyl, piperidyl, O-M,

CH ₂-(CH ₂) _q-M, O-(CH ₂) _q-M, (CH ₂) _q-O-M and CH=CH-M; R wherein ₅And R ₆

Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl and benzyl,

Perhaps R ₅And R ₆Can be joined together to form 5-or 6-unit heterocycle; M is selected from the 4-methoxy

Base phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, pyranose (pyrazyl), quinoline

Base, 3,5-dimethyl isoxazole base (dimethylisoxazoyl), isoxazolyl

(isoxazoly), 2-methylthiazol base, thiazolyl, 2-thienyl, 3-thienyl and pyrimidine

Base; Q is 0 to 2 integer; And wherein Y has one or more being independently selected from

Following substituent group: hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy,

C ₁-C ₆Alkyl, C ₁-C ₆Alkenyl, O-(C ₁-C ₄Alkyl), O-(C ₂-C ₄Alkenyl), O-

Benzyl, O-phenyl, 1,2-methylene-dioxy, amino and carboxyl;

(viii) m is 0 to 3 integer; And

(b) pharmaceutical carrier.

2. the process of claim 1 wherein that J and K are joined together to form 5-, 6-or 7-unit heterocycle, m is 0 to 1 integer.

3. the method for aforementioned each claim, wherein J and K are joined together to form 5-, 6-or 7-unit heterocycle, and this heterocycle comprises other hetero atom that is selected from S, O, NH and NE.

4. claim 1 or 2 method, wherein said chemical compound have and are selected from following structure:

Wherein G, L and M are selected from CH independently of one another ₂, S, O, NH and NE.

5. claim 1 or 2 method, wherein said chemical compound have and are selected from following structure:

Wherein G, L and M are selected from CH independently of one another ₂, S, O, NH and NE.

6. claim 1 or 2 method, wherein said chemical compound has following array structure:

Wherein

(a) R ₁₂Be selected from hydrogen and-(CH ₂) _t-R ₁₆, wherein t is 1 to 3 integer, R ₁₆Be selected from Ar and

NR ₁₇R ₁₈, R wherein ₁₇And R ₁₈Be selected from hydrogen, C independently of one another ₁-C ₅Alkyl and-(CH ₂)-Ar,

Perhaps R ₁₇And R ₁₈Can be joined together to form 5-or 6-unit heterocycle;

(b) R ₁₃, R ₁₄And R ₁₅Be selected from hydrogen, halogen, C independently of one another ₁-C ₆Alkyl, O-(C ₁-C ₆Alkyl),

-(CH ₂) _e-Ar and-G (CH ₂) _e-Ar, wherein e is 0 to 4 integer; G is selected from O, S and NR ₁₉,

R wherein ₁₉Be selected from hydrogen and C ₁-C ₆Alkyl; With

(c) A be selected from-O-and-NH-.

7. the method for claim 6, wherein

(a) R ₁₃And R ₁₅Be selected from independently of one another-OCH ₂-4-pyridine ,-O-propyl group and hydrogen;

(b) R ₁₄Be selected from-OCH ₂-4-pyridine, methyl and hydrogen;

(c) R ₁₂Be selected from-CH ₂-3-pyridine and hydrogen;

(d) A is selected from O, NH ₂With the N-benzyl; With

(e) X is 3,4, the 5-trimethoxyphenyl.

8. the method for claim 7, wherein

(a) R ₁₃And R ₁₅Be selected from independently of one another-OCH ₂-4-pyridine ,-O-propyl group and hydrogen;

(b) R ₁₄Be selected from-OCH ₂-4-pyridine, methyl and hydrogen;

(c) R ₁₂Be selected from-CH ₂-3-pyridine and hydrogen;

(d) A is selected from O, NH ₂With the N-benzyl; With

(f) X is 3,4, the 5-trimethoxyphenyl.

9. the method for aforementioned each claim, wherein administration is a topical.

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