CN101426782B

CN101426782B - Melanocortin type 4 receptor agonist piperidinoylpyrrolidines

Info

Publication number: CN101426782B
Application number: CN2007800145719A
Authority: CN
Inventors: 马克·D·安德鲁斯; 艾伦·D·布朗; 马克·I·兰斯德尔; 尼古拉斯·W·萨默希尔
Original assignee: Pfizer Ltd
Current assignee: Pfizer Ltd
Priority date: 2006-02-23
Filing date: 2007-02-19
Publication date: 2012-10-31
Anticipated expiration: 2027-02-19
Also published as: JP2009527543A; JP5243274B2; CN101426782A; ZA200806992B

Abstract

The present invention relates to a class of melanocortin MCR4 agonists of general formula (I), wherein the variables and substituents are as defined herein and especially to selective MCR4 agonist compounds, to their use in medicine, particularly in the treatment of sexual dysfunction and obesity, to intermediates useful in their synthesis and to compositions containing them.

Description

Melanocortin 4 receptor agonist piperidinyl carbonyl tetramethyleneimine

The present invention relates to the compound of some types; With its pharmaceutically acceptable salt, solvate and prodrug; They are melanocortin 4 (MC4) receptor stimulants, and particularly selectivity MC4 agonist compound the present invention relates to its purposes in medicine; Relate to said compound compositions, relate to their method of preparation and relate to the midbody that uses in these methods.Special, the present invention relates to MCR4 agonist class piperidinyl carbonyl tetramethyleneimine (piperidinoylpyrrolidines) compound, said compound is used for therapeutic dysfunction, obesity, mellitus and other disease.[term " MC4 ", " MC4 acceptor " " MCR4 ", " MC4-R " etc. are in the interchangeable use of this paper.]

Melanocortin is pro-opiomelanocortin (POMC) the deutero-peptide of the G-protein linked receptor that combines and activate melanocortin receptor family (GPCR ' s).Melanocortin is regulated many physiological processs, comprises sexual function and sexual behaviour, ingestion of food and metabolism.Cloned 5 kinds of melanocortin receptors, MCR1, MCR2, MCR3, MCR4, MCR5, and they are expressed in multiple tissue.MCR1 expresses in melanocyte and MC specifically; MCR2 is ACTH receptor and in adrenal tissue, expresses; MCR3 mainly expresses in brain and limbic system; The MCR4 wide expression is in brain and spinal cord, and MCR5 is expressed in brain and the many peripheral tissues, comprises skin, fatty tissue, Skelettmuskel and Lymphoid tissue.MCR3 possibly participate in controlled function, ingestion of food and heat production.

MC4-R is seven transmembrane receptors of G albumen coupling, mainly is expressed in (people 1993J Biol Chem 268:15174-15179 such as Gantz) in hypothalamus, hippocampus and the thalamus.This receptor is participated in the maincenter of body weight and regulated: MC4-R is activated by the α-melanocyte-stimulating hormone (MSH) derived from pro-opiomelanocortin, and agouti gene-correlation albumen (AGRP) can make this receptor inactivation.α-MSH induces weight loss, yet the proteic ectopic expression of agouti causes obesity (the people 1993Nature 385:165-168 such as Fan in the agouti mouse; Lu et al.1994Nature 371:799-802).Other evidence of MC4-R effect in body weight is regulated is from gene knock-out mice model people 1997 Cell 88:131-141 such as () Huszar (the people 1998Nat Genet 20:113-114 such as Vaisse that suddenlys change with people's haplo-insufficiency; People 1998NatGenet 20:111-112 such as Yeo; People such as Hinney 1999 J Clin Endocrinol Metab 84:1483-1486).In the MC4-R-knock-out mice, can be observed 5 the week age mouse weight increase.To 15 weeks, homozygous mutation female mice mean body weight is the twice of the brood mouse of wild-type, and the homozygous mutation male mice than wild control mice heavy～50%.MC4-R knocks out increase that the heterozygote mouse shows body weight between the weight increase of wild-type and homozygous mutation mouse, shows that therefore MC4-R removes the dosage effect of gene that body weight is regulated.Increase～50% people 1997 Cell 88:131-141 such as () Huszar is compared in the ingestion of food of homozygote sudden change with the wild-type relatives.[from Am.J.Hum.Genet., 65:1501-1507,1999].The activation that has shown MCR4 can be induced the erection in the rodents, the inactivation of MCR4 can cause fat (at Hadley, 1999, Ann N Y Acad Sci. summarizes among the 885:1-21, people such as Wikberg 2000, Pharmacol Res., 42 (5), 393-420).

At Drugs Of The Future, 2004,29 (10): among the 1065-1074, Chaki and Nakazato point out to act on the potential treatment of the part of MC4 acceptor and use.International Patent Application Publication No. WO2005/077935, WO02/068387 and WO02/068388; And International Patent Application PCT/IB2006/002151 relates to specific piperidino carbonyl tetramethyleneimine MC4 agonist, and it can be used for therapeutic dysfunction, obesity, mellitus and other disease.For the treatment aspect of MC4 agonist of the present invention, above-mentioned being disclosed in here all quoted as a reference.

Compound of the present invention is used to treat disease, illness or the state of an illness that the MC4 receptor activation is responded, and comprising:

The masculinity and femininity sexual dysfunction comprises hypoactive dysaphrodisia, sexual arousal dysfunction, female orgasmic disorder and/or sexual pain disorder, male erectile dysfunction;

Fat (through reducing appetite, increase accretion rate, reduce the fat picked-up or reducing sugar craving); With

Mellitus (through increasing the glucose tolerance and/or reducing insulin resistant).

Compound of the present invention can be used for treating other disease, illness or the state of an illness, include, but are not limited to hypertension, hyperlipidaemia, osteo-arthritis, cancer, gallbladder disease, sleep apnea, dysthymia disorders, anxiety, obsession, neuropathy, insomnia/sleep disease, drug dependence, pain, heating, inflammation, immunomodulatory, rheumatoid arthritis, skin tanning, acne and other dermatosis, neuroprotective and cognitive hypermnesia comprise treatment alzheimer's disease, treatment lower urinary tract dysfunction (comprise the urinary incontinence-overactive bladder, day frequency increase, nycturia, urgent urination, the urinary incontinence (the leakage of urine state of an illness is unintentionally arranged) comprise stress incontinence, urge incontinence and the mixing urinary incontinence, the overactive bladder of following the urinary incontinence, the enuresis, nocturnal enuresis, the persistence urinary incontinence, the situation property urinary incontinence for example during sexual intercourse the urinary incontinence and follow the lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH)) and the above-mentioned patented claim that relates in other indication of mentioning.

Compound of the present invention is particularly suitable for treating Female sexual dysfunction, male erectile dysfunction, obesity, mellitus and the lower urinary tract dysfunction state of an illness.

Term as used herein " treatment " (＂ treating ＂, ＂ treat ＂ or ＂ treatment ＂) comprises prevention and control, promptly specifies the prevention and the remissive treatment of the state of an illness.

The desirable properties of compound MCR4 agonist of the present invention comprises: ideal MCR4 agonist is renderd a service, as hereinafter detailing; Compare with MCR1 and/or MCR5 and/or MCR3, to the selectivity of MCR4 agonism, as hereinafter detailing; Ideal MC4R agonist is renderd a service and is compared the selectivity of MCR4 with MCR1 and/or MCR5 and/or MCR3; Good biopharmacy character, for example physical stability; Solubleness; Oral administration biaavailability; Suitable metabolic stability; Substitute the ability of AGRP from the MC4 acceptor.

The invention provides the compound of formula (I), and pharmaceutically acceptable salt, solvate (comprising hydrate) and prodrug,

Wherein

One among X and the Y is N, and another is CH,

R is F, Cl, CN, CF ₃Or methoxyl group, condition is when Y is N, R is not F or Cl,

R ¹Be phenyl, 2-pyridyl, C ₃-C ₆Naphthenic base or CH ₂(C ₃-C ₆Naphthenic base), wherein loop section is optional is replaced by one or more substituting groups, and said substituting group is independently selected from F, Cl, CN, methyl and methoxyl group,

R ²Be H, F or Cl, condition is when Y is N, R ²Not F or Cl,

Het is the 6-unit ring that contains 1 or 2 N atom, and wherein this encircles and is aromatic nucleus, or in ring, contains 2 two keys and=O substituting group, and this ring is optional to be replaced by one or more substituting groups, and said substituting group is independently selected from F, Cl, OH, CN, methyl, ethyl, NH ₂, NHCH ₃, N (CH ₃) ₂And methoxyl group,

Perhaps, Het is the 6-unit ring that contains 1 or 2 N atom, this 6-unit ring with respect to link to each other with pyrrolidine ring 3, the 4-position condenses with the 5-unit aromatic nucleus that contains one or two other N atom, this 5-unit ring is chosen wantonly and is replaced by OH.

The limiting examples of suitable " Het " group is as follows:

Preferably X is that N and Y are CH.

Preferably R is a chlorine.

R preferably ¹By the substituted phenyl of one or more substituting groups, said substituting group is independently selected from F, Cl, CN, methyl and methoxyl group for optional.

R more preferably ¹Be phenyl, 4-chloro-phenyl-or 4-fluorophenyl.

In another embodiment, R ¹Be preferably C ₃-C ₆Naphthenic base more preferably is cyclopropyl or cyclohexyl.

R preferably ²Be H or F.

R more preferably ²Be H.

Preferably Het is pyridine-2-base, pyridin-3-yl, pyridazine-3-base, 6-oxo-1,6-dihydrogen dazin-3-base, 6-oxo-1,6-dihydropyridine-3-base, 2-oxo-1; 2-dihydro-pyrimidin-4-base, 6-oxo-1,6-dihydro-pyrimidin-4-base, 2-oxo-1,2-dihydropyridine-4-base, imidazo [1; 2-b] pyridazine-6-is basic, [1,2,4] triazolo [4; 3-b] pyridazine-6-base or 6-oxo-1; 6-dihydropyridine-2-base, it is optional by one or more substituting groups replacements, and said substituting group is independently selected from F, Cl, OH, CN, methyl, ethyl and methoxyl group.

More preferably Het is pyridine-2-base, pyridin-3-yl, pyridazine-3-base or 6-oxo-1,6-dihydrogen dazin-3-base, and it is optional by one or more substituting groups replacements, and said substituting group is independently selected from OH, CN, F, methyl and methoxyl group.

More preferably Het is pyridine-2-base or pyridazine-3-base, each with respect to the contraposition of the key that partly links to each other with tetramethyleneimine by OH, CN or methoxyl group replacement.

Most preferably Het is a pyridazine-3-base, its with respect to the contraposition of the key that partly links to each other with tetramethyleneimine by OH, CN or methoxyl group replacement.

Preferred compound, salt, solvate and prodrug comprise such compound, wherein:

R ¹Have the value (value) relevant with following particular compound.

Preferred compound, salt, solvate and prodrug comprise such compound, wherein:

R has the value relevant with following particular compound.

Preferred compound, salt, solvate and prodrug comprise such compound, wherein:

R ²Have the value relevant with following particular compound.

Preferred compound, salt, solvate and prodrug comprise such compound, wherein:

Het has the value relevant with following particular compound.

Other preferred compound, salt, solvate and prodrug comprise such compound, wherein:

R, R ¹, R ²Have the value relevant with Het with following particular compound.

Preferably said compound is selected from:

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-3,5-dimethyl--4-Phenylpiperidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-3,5-dimethyl--4-pyridine-2-phenylpiperidines-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-3,5-dimethyl--4-Phenylpiperidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-3,5-dimethyl--4-Phenylpiperidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-chloropyridine-2-yl) tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(5-chloropyridine-2-yl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(3, the 4-difluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-4-(4-p-methoxy-phenyl)-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-cyclohexyl-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

(3R, 4R, 5S)-1-{ [(3S, 4S)-1-(6-chlorine pyridazine-3-yl)-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(6-methoxyl group pyridazine-3-yl) tetramethyleneimine-3-yl] carbonyl }-4-cyclopropyl-3,5-lupetidine-4-alcohol;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(5-fluorine pyridin-3-yl) tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-the 3-cyanopyridine;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-fluorine pyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-fluorine pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-hydroxyl-3,5-dimethyl--4-Phenylpiperidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-fluorine pyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-fluorine pyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-cyanopyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4R)-3-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(6-methoxypyridine-3-yl) tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-methoxypyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3-nitrile;

(3R, 4R, 5S)-4-(4-fluorophenyl)-1-{ [(3S, 4R)-1-(5-fluorine pyridin-3-yl)-4-(6-methoxypyridine-3-yl) tetramethyleneimine-3-yl] carbonyl }-3,5-lupetidine-4-alcohol;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-pyridazine-3-base tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-[1,2,4] triazolo [4,3-b] pyridazine-6-base tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-imidazo [1,2-b] pyridazine-6-base tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

4-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyrimidine-2 (1H)-ketone;

4-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-1-methylpyrimidine-2 (1H)-ketone;

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(6-methoxyl group pyridazine-3-yl) tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol;

6-[(3S, 4S)-3-(5-chloro-3-fluorine pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-chloro-3-fluorine pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine, 1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloro-3-fluorine pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(3,5-difluoro pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(3,5-difluoro pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(3,5-difluoro pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-chloropyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(3, the 4-difluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile;

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-chloropyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(3, the 4-difluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

And pharmaceutically acceptable salt, solvate (comprising hydrate) and prodrug.

More preferably said compound is selected from:

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(5-chloropyridine-2-yl)-4-hydroxyl-3,5-lupetidine, 1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloro-3-fluorine pyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone;

And pharmaceutically acceptable salt, solvate (comprising hydrate) and prodrug.

Most preferably said compound is selected from:

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl }-4-(5-chloropyridine-2-yl) tetramethyleneimine, the 1-yl]-2-methyl pyridazine-3 (2H)-ketone;

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine, 3 (2H)-ketone;

And pharmaceutically acceptable salt, solvate (comprising hydrate) and prodrug.

The pharmaceutically acceptable salt of formula (I) compound comprises its acid salt.The acid salt that is fit to forms from acid, and this acid forms nontoxic salt.Instance comprises acetate; Adipate; Aspartate; Benzoate; Benzene sulfonate; Bicarbonate/carbonate; Hydrosulfate/vitriol; Borate; Camsilate; Citrate trianion; Cyclamate; Ethanedisulphonate; Esilate; Formate; Fumarate; Gluceptate; Glyconate; Glucuronate; Hexafluorophosphate; Hybenzate; Hydrochloride/muriate; Hydrobromate/bromide; Hydriodate/iodide; Isethionate; Lactic acid salt; Malate; PHENRAMINE MALEATE; Malonate; Mesylate; Methylsulfate; Naphthoate (naphthylate); The 2-naphthalenesulfonate; Nicotinate; Nitrate salt; Orotate; Oxalate; Palmitate; Pamoate (pamoate); Phosphate/phosphor acid hydrogen salt/dihydrogen phosphate; Pyroglutamate; Saccharate; Stearate; SUMATRIPTAN SUCCINATE; Tannate; Tartrate; Tosylate; Trifluoroacetate and xinafoate (xinofoate).Can also form half salt (hemisalts) of acid, for example Hemisulphate (hemisulphate).For the summary of suitable salt, referring to Handbook of Pharmaceutical Salts:Properties, Selection and Useby Stahl and Wermuth (Wiley-VCH, 2002).

Compound of the present invention, salt, solvate and prodrug can exist with tautomer (tautomeric), zwitter-ion, polymorphic, crystal, liquid crystal forms such as (liquid crystalline).All these forms is included in the scope of the present invention.The instance (compound is an example with " Het " group) of expression tautomer relation is as follows, and " ketone " and " enol " tautomer is included in the scope for " Het " of formula (I) compound:

Also comprise multicomponent mixture (except salt and solvate) in the scope of the present invention, its Chinese traditional medicine and at least a other composition exist with stoichiometry or non--stoichiometry.This type mixture comprises inclusion compound (clathrate) (drug-host's mixture) and cocrystallization (co-crystals).The latter is normally defined the crystalline state mixture of neutral molecule (neutral molecular) composition that links together through noncovalent interaction, but also can be the mixture of neutral molecule and salt.

Also comprise isotope-labeled formula (I) compound in the scope of the present invention, for example, wherein mix ²H, ³H, ¹³C, ¹⁵N, ¹⁸O or other isotropic substance, this can use the method preparation of methods known in the art and reagent or its change through the suitable variation of compound method as herein described.

As shown here, so-called ' prodrug ' of the compound of formula (I) within the scope of the invention.Therefore, when some verivates (itself can have or not have pharmacological activity hardly) with formula (I) compound are administered in the body or on the health time, said verivate can change into and has required active formula (I) compound, for example passes through hydrolytic cleavage.These verivates refer to ' prodrug '.For the further information of the purposes of prodrug referring to Pro-drugs as Novel Delivery Systems, Vol.14, ACS SymposiumSeries (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, PergamonPress, 1987 (Ed.E B Roche, American Pharmaceutical Association).

The compound of some formulas (I) itself can also be as the prodrug of other formula (I) compound.

The routine techniques of the single enantiomorph of preparation/separation comprises from being fit to optically pure precursor chirality synthetic or for example use that chiral high performance liquid chromatography (HPLC) carries out the fractionation of racemic modification (or racemic modification of salt or verivate).

Perhaps; Racemic modification (or racemize precursor) can react with the optically active compound that is fit to, said optically active compound, for example alcohol; Or contain under the situation of acidity or basic moiety at the compound of formula (I), with acid or alkali such as tartrate or the reaction of 1-phenyl ethyl amine.The gained non-enantiomer mixture can separate through chromatogram and/or fractional crystallization, or through the known method of technician two kinds of diastereomers is converted into corresponding one or more pure enantiomorphs.

Chipal compounds of the present invention (with its chiral precurser) can use chromatography (being generally HPLC) usefulness on asymmetric resin to contain the Virahol (being generally 2 to 20%) of 0 to 50% volume in being rich in enantiomeric form and can contain the moving phase acquisition of hydrocarbon (being generally heptane or the hexane) composition of the alkylamine of 0 to 5% volume.The concentration of elutriant provides the mixture that is rich in.The absolute compsn of moving phase will depend on selected chiral stationary phase (asymmetric resin).

Following approach in being included in embodiment and preparing is represented the method for the compound of synthesis type (I).The technician will understand compound of the present invention, and their midbody can be through the method beyond the specifically described method of this paper, and for example through the change of methods described herein, for example methods known in the art prepare.For synthetic, functional group transforms, the instruction that is fit to of the use of protection base etc. referring to, for example:

" Comprehensive Organic Transformations ", RC Larock, VCH PublishersInc. (1989); Advanced Organic Chemistry " by J.March, Wiley Interscience (1985); " Designing Organic Synthesis " by S Warren, Wiley Interscience (1978); " Organic Synthesis-The Disconnection Approach ", S Warren, WileyInetrscience (1982); " Guidebook to Organic Synthesis ", RK Mackie and DMSmith, Longman (1982); " Protective Groups in Organic Synthesis ", TW Greene and PGM Wuts, John Wiley and Sons, Inc. (1999); " Protecing Groups ", PJ, Kocienski, Georg Thieme Verlag (1994); Any improved version with said standard method.

In following common compound method, removing other has explanation, substituent R, R ¹, R ², X, Y and Het such as above-mentioned referring to definition for the compound of formula (I).

Following approach is represented the method for the compound of synthesis type (I).The technician will understand also can use other method of equal value.

Scheme 1 representes to prepare through midbody (II) and peptide coupling (III) compound of formula (I), if desired, adds the alkali and/or the additive (for example I-hydroxybenzotriazole hydrate or 4-dimethylaminopyridine) that are fit to.

Scheme 1

Acid and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), triethylamine or N-methylmorpholine and the I-hydroxybenzotriazole hydrate (HOBt) that the condition of perhaps using comprises the piperidines that at room temperature stirs general formula (II) and general formula (III) be the solution in N (DMF), THF (THF), methylene dichloride (DCM) or ETHYLE ACETATE (EtOAc) together.Other selectable suitable method midbody compound and general formula (III) and O-benzotriazole-1-base-N for stirring general formula (II), N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) or 1-propyl group phosphoric acid cyclic acid anhydride are together at CH ₂Cl ₂Or the solution among the EtOAc.Any suitable inert solvent can be used for above-mentioned condition, and wherein inert solvent refers to not contain the solvent of carboxylic acid or primary amine or secondary amine.Should use at least 1 normal every kind of coupling reagent, and optionally can use one or both excessive coupling reagents.

According to another embodiment, the invention provides novel general formula (III) midbody compound.

Scheme 2 has been explained the another kind of approach for preparing general formula (I) compound through the method for using the protection base, and said compound has a series of Het group.

Scheme 2

Nitrogen-protection the base of PG for being fit to.

Novel formula (IV), (V) and (VI) compound be another embodiment of the invention.

In scheme 2; Use peptide coupling method coupling general formula (II) the amine midbody of standard described in the such scheme 1 and the link coupled and the midbody of protection of protected pyrrolidine acid midbody to prepare logical formula V of general formula (IV), the deprotection scheme of use standard removes nitrogen-protecting group to obtain the compound of general formula (VI) from lead to formula V.Can use any suitable nitrogen-protecting group (like " Protecting Groups inOrganic Synthesis " 3 ^RdEdition T.W.Greene and P.G.Wuts, Wiley-Interscience is described in 1999).Nitrogen-protecting group suitable used herein (PG) commonly used comprises tert-butoxycarbonyl (t-Boc), and it is through removing to convenient processing at organic solvent (like methylene dichloride or 1, the 4-diox) with acid (like trifluoroacetic acid or hydrochloric acid); And benzyl, it is removed through hydrogenation in the presence of the catalyzer that is fit to or through handling with chloroformic acid 1-chloro-ethyl ester.

" Het " group (wherein " Het " is heteroaryl) can be introduced through replacing suitable leavings group, the leavings group that for example replacement is fit to from the assorted fragrant precursor of formula " Het-L ", the wherein leavings group of L for being fit to.The leavings group that is fit to comprises halogen.In some cases, possibly need transition-metal catalyst (like palladium, copper), optional and phosphine part (as 1,1 '-dinaphthyl-2,2 ' two basic dibiphenylyl phosphines) combination is to obtain required coupled product.

Perhaps, general formula (I) compound that has a concrete Het group can be converted into other general formula (I) compound with different Het groups.For example:

I) compound of formula (Ia), wherein Het contains suitable leavings group L described in scheme 3, and like methoxyl group or chlorine, this formula (Ia) compound can be converted into formula (Ib) compound through hydrolysis under acidity or alkaline condition described in scheme 3.The preferred acidic condition, and especially preferably use acetate processing formula (Ia) compound under reflux temperature.Perhaps, formula (Ia) compound (wherein L is a chlorine) can with formula Z-O ^-Alkoxide (the wherein oxygen protection base of Z) reaction for being fit to, obtain formula (Ia) midbody, wherein L is OZ.Deprotection provides the compound of formula (Ib) then.For example, when the Z=benzyl, it can remove through hydrogenation in the presence of suitable catalyzer.

Scheme 3

Ii) described in scheme 4, formula Ic compound is (wherein described in Het such as the scheme 4 and R ³Be H) can be converted into formula Id compound through handling in being fit to solvent, R wherein with alkali and alkylating reagent ³Be methyl or ethyl.The alkali that is fit to comprises sodium hydride, lithium diisopropylamine (lithiumdiisopropylamide) and hexamethyl two silica-based sodium amides (sodium hexamethyldisilazide); The alkylating reagent that is fit to comprises methyl-iodide, toluenesulphonic acids methyl esters, methyl-sulfate and iodoethane, and the solvent that is fit to comprises THF, N and N-N-methyl-2-2-pyrrolidone N-.Optional additive, like lithium salts, for example lithiumbromide also may reside in the reaction mixture.

Scheme 4

Scheme 5 has been explained from the approach of undersaturated general formula (VII) intermediate preparation general formula (IV) pyrrolidine acid midbody.

Scheme 5

The nitrogen-protecting group of PG for being fit to.PG ²Be the carboxylic acid protecting group who is fit to.Formula (VIII), (IX), (X), (XI) and (XII) compound promptly can be commercially available also can be known with document as herein described and/or preparation those skilled in the relevant art.

The compound of general formula (VII) can use suitable ylide (like methyl (the inferior phosphoranyl (triphenylphosphoranylidene) of triphenyl) acetic ester or phosphonic acid ester (phosphonate) negatively charged ion, like the deprotection from trimethyl phosphono acetate (trimethylphosphonoacetate)) to become to be mainly required trans-isomer(ide) through Wittig or similar approach alkylene general formula (XI) aldehyde intermediate preparation.

Many selectable methods that are used to prepare the unsaturated midbody of general formula (VII) are arranged in document; Comprise and use standard method protection precursor cinnamic acid derivative (VIII); Or at palladium catalyst and the alkali (like triethylamine) that is fit to down, the Heck of aromatic halides (IX) and suitable acrylate derivative (X) (for example tert-butyl acrylate) reacts.

Gained general formula (VII) E-alkene midbody will experience the cycloaddition of [3+2]-azomethine ylide through the ylide precursors reaction with general formula (XII), obtain almost unique trans stereochemical tetramethyleneimine that is.This reaction needed inert solvent, like methylene dichloride or toluene or THF and the activation through one or more following conditions: (1) acid catalyst, like TFA; (2) desiliconization alkanisation reagent is like tachyol; (3) heating.

The compound of the general formula (XIII) that obtains from cycloaddition reaction is a racemic modification, and can split and obtain it and form enantiomorph (constituent enantiomers), and said fractionation can use chiral stationary phase to realize through preparation HPLC.Perhaps, the sour midbody of general formula (IV) can split through standard method, for example forms non-enantiomer derivative through the reagent react with enantiomer-pure, and the gained diastereomer is through physical method for separation, and leaving away then obtains acid (IV).

The midbody compound of general formula (XIII) can be through the basic PG of protection ²Deprotection be converted into the compound of general formula (IV).Many methods can be used to realize this conversion (referring to Advanced OrganicChemistry:Reactions, Mechanisms, and Structure, Fourth Edition.March; Jerry, 1992, pp378-383; Wiley, New York, N.Y.USA publishes).Especially, for alkali labile protection base, the compound of in appropriate organic solvent, handling general formula (XIII) with alkali metal hydroxide aqueous solution (like Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide) obtains corresponding general formula (IV) compound.Preferably, organic cosolvent that can be miscible with water (for example 1,4-diox or THF) also can use in this type reaction.If desired, can reacting by heating to help hydrolysis.Under acidic conditions, some protection bases be more convenient for hydrolysis, the for example tertiary butyl or benzhydryl esters (benzhydryl esters).These esters can be through being used in anhydrous acid such as trifluoroacetic acid or the salt s.t. in the inert organic solvents (like methylene dichloride).

The compound of novel formula (XIII) is another embodiment of the present invention.

Scheme 6 has been explained the approach of another kind from the single enantiomorph of the pyrrolidine acid midbody of the unsaturated intermediate preparation general formula (IV) of general formula (VII), and this approach Shi Yong oxazolidone is as the chirality subsidiary.The acid of formula (VIII) can obtain through deprotection (VII), is converted into mixed acid anhydride then, (the R preferably wherein of Yu oxazolidone coupling then ⁴Be phenyl, the tertiary butyl or sec.-propyl) obtain the midbody of formula (XIV).Perhaps, formula (VII) compound is (as working as PG ²) during=OCOt-Bu is Yu the lithium salts of oxazolidone, and reaction also can obtain the compound of formula (XIV) in the solvent (like THF) that is fit to.

The compound of formula (XIV) will be through experiencing the cycloaddition of [3+2]-azomethine ylide with the reaction of general formula (XII) compound; Obtain diastereomer (XV) and (XVI); They can separate through chromatography or crystallization process, and hydrolysis obtains the tetramethyleneimine of formula (IV) then.Perhaps, the compound of general formula (XVI) can be converted into the compound of general formula (XIII), and the sodium methylate processing that for example is used in the methylcarbonate (is worked as PG ²During=OMe).

Scheme 6

PG is selected from suitable nitrogen-protecting group.PG ²Be selected from suitable carboxylic acid protecting group, and use different groups with (XIII) for compound (VII).

Novel formula (XVI) compound is another embodiment of the present invention.

Scheme 7 has been explained from the approach of the pyrrolidine acid midbody of the intermediate preparation general formula (III) of general formula (XIII).In case when using any suitable routine techniques to remove the basic PG of protection, can introduce the Het group through the appropriate methodology described in the scheme 2.Then like the scheme 4 said basic PG of acid protection that remove ², obtain the acid of general formula (III).

Scheme 7

PG is selected from suitable nitrogen-protecting group.PG ²Be selected from suitable carboxylic acid protecting group.

Novel formula (XVII) and (XVIII) compound be another embodiment of the present invention.

Described in scheme 8, the piperidines midbody of general formula (II) can obtain general formula (XX) midbody through addition organo-metallic nucleophilic reagent in the ketone of the general formula that contains suitable nitrogen-protecting group (PG) (XIX) and prepare.The stereochemistry of addition makes that preferably the hydroxyl in the product is a cis for two methyl.To the controlled addition (for example described this) of carbonyl system be described in the document (like Journal of MedicinalChemistry (1964), 7 (6), pp726-8).These nucleophilic addition(Adn)s are carried out in anhydrous ether or other non-polar solvent usually at low temperatures, and Grignard reagent, organolithium reagent or other organometallic reagent that is fit to are used in this addition.These organometallic reagents can be through using the halide precursors (R that is fit to ¹-Br or R ¹-I) halogen-metal exchange with n-Butyl Lithium or tert-butyl lithium prepares.The protection base that is fit to comprises benzyl, and it is removed through hydrogenation; Or Boc, it is removed through handling like TFA with acid; Or to methoxy-benzyl (PMB), it is removed through handling with DDQ, CAN or chloroformic acid 1-chloro-ethyl ester, obtains the piperidines midbody of required general formula (II).For some protection bases, and under certain condition, said protection base is unstable for handling with organometallic reagent; And two conversions can realize in a step; For example when PG=Boc, when formula (XIX) midbody is handled with organometallic reagent, this protection base can be left away sometimes.

Scheme 8

PG is selected from suitable nitrogen-protecting group.

The technician will understand, and except that protection nitrogen or acid groups, as stated, during synthetic compound of formula i, other group that needs protection for example with the protection base protection hydroxyl that is fit to, removes the protection base then under many circumstances.The method of the deprotection of any special groups will depend on the protection base.The instance of learning for protection/deprotection method is referring to " Protective groups in Organic synthesis ", TW Greene and PGM Wutz.For example, wherein hydroxyl is protected and is methyl ether, and the deprotection condition can for example be included in 48% the HBr aqueous solution and reflux, or through stirring with boron tribromide in methylene dichloride.Perhaps, wherein hydroxyl is protected and is benzylic ether, and the deprotection condition can for example comprise with palladium catalyst hydrogenation in nitrogen atmosphere.

The preparation of used novel starting substance is conventional in all above-mentioned reactions and the aforesaid method, and will be known for the technician in the field of the literature method that relates to this paper and embodiment and preparation for their carrying out or preparation and the suitable reaction conditions that separates the method for required product.

The pharmaceutically acceptable salt of formula (I) compound can be mixed together through the solution with formula (I) compound and required acid optionally and preparation fast.This salt can be precipitated out from solution, and collects through filtering, and maybe can reclaim through evaporating solvent.

The pharmaceutically acceptable salt of formula (I) compound can be through one or more preparations in following three kinds of methods:

(i) make the compound and the required acid-respons of formula (I);

(ii) remove disacidify-or alkali-unsettled protection base from the suitable precursor of the compound of formula (I), or through using required acid to make suitable ring precursor, for example lactone or lactan open loop; Or

(iii) through a kind of salt of the compound of formula (I) being converted into another kind with the acid-respons that is fit to or through suitable ion exchange column.

All three kinds of reactions are carried out in solution usually.Gained salt is precipitable to come out and collects through filtering, and maybe can reclaim through evaporating solvent.Degree of ionization in gained salt can change from ionize fully to ionize hardly.

The compound of formula of the present invention (I) is used to treat various disease states as the MCR4 agonist.Preferably, said MCR4 agonist shows the functional effectiveness (functional potency) to the MC4 acceptor, is expressed as EC ₅₀, be lower than about 1000nM, more preferably be lower than 500nM, yet more preferably be lower than about 100nM, and more preferably even be lower than about 50nM, the EC that wherein said MCR4 function is renderd a service ₅₀Measurement can use the method E among the International Patent Application Publication No. WO2005/077935 to carry out.Make in this way, compound according to the present invention shows functional effectiveness to the MC4 acceptor, is expressed as EC ₅₀, be lower than about 1000nM.

The preferred compound of this paper shows like defined functional effectiveness to the MC4 acceptor before this paper, and the selectivity of MCR4 is surpassed MCR1.Preferably; Said MCR4 agonist surpasses MCR1 to the selectivity of MCR4; Wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to the MCR1 acceptor at least about 10 times, at least about 20 times, more preferably at least about 30 times in addition more preferably at least about 100 times, especially more preferably at least about 300 times even more preferably at least about 500 times; Especially at least about 1000 times, wherein said relative selectivity evaluation is based on the mensuration to the function effectiveness of MCR1 and MCR4 of using that method described herein carries out.

Preferably; Said MCR4 agonist surpasses MCR3 to the selectivity of MCR4; Wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to the MCR3 acceptor at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times; Even more preferably at least about 500 times; Especially at least about 1000 times, wherein said relative selectivity evaluation is based on the mensuration to the function effectiveness of MCR3 and MCR4 of using that method described herein carries out.

The preferred compound of this paper shows like defined functional effectiveness to the MCR4 acceptor before this paper, and the selectivity of MCR4 is surpassed MCR5.Preferably; Said MCR4 agonist surpasses MCR5 to the selectivity of MCR4; Wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to the MCR5 acceptor at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times even more preferably at least about 500 times; Especially at least about 1000 times, wherein said relative selectivity evaluation is based on the mensuration to the function effectiveness of MCR5 and MCR4 of using that method described herein carries out.

Preferably; Said MCR4 agonist surpasses MCR1 and MCR3 to the selectivity of MCR4, wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to MCR1 and MCR3 acceptor at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times even more preferably at least about 1000 times.

The preferred compound of this paper shows like defined functional effectiveness to the MCR4 acceptor before this paper, and the selectivity of MCR4 is surpassed MCR1 and MCR5.Preferably; Said MCR4 agonist surpasses MCR1 and MCR5 to the selectivity of MCR4; Wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to MCR1 and MCR5 acceptor at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times even more preferably at least about 500 times, especially at least about 1000 times.

Preferably; The selectivity of said MCR4 agonist MCR4 surpasses MCR3 and MCR5, wherein said MCR4 receptor stimulant to the functionally selected property of MCR4 acceptor be to MCR3 and MCR5 acceptor at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times, most preferably at least about 1000 times.

Combined therapy

Formula of the present invention (I) compound or their salt, solvate or prodrug can be used for the combination of the auxiliary effective promoting agent of the treatment of conditions paid close attention to sent said illness such as sexual dysfunction, lower urinary tract disorders, obesity and/or mellitus.And in some cases, the compound of formula of the present invention (I) or their salt, solvate or prodrug can be used for sending with the effective active agent combination that helps to alleviate vomiting.The auxiliary effective active agent that some that use in the compsn of the present invention are fit to comprises:

1) regulates short natriuretic factor; Especially the compound of the effect of ANF (being also referred to as Natriuretic factor, atrial); Type B and C type are urged natriuretic factor; Described in suppressor factor or Proteinase, kidney brush border neutral and especially WO02/02513, WO02/03995, WO02/079143 and EP-A-1258474 and claimed compounds, and compound (2S)-2{ of the embodiment 22 of WO02/079143 [1-{3-4 (chloro-phenyl-) propyl group] amino especially carbonyl)-cyclopentyl] methyl }-4-methoxyl group butyric acid;

2) compound such as the enalapril of inhibition angiotensin-converting enzyme, and the composite restrainer of angiotensin-converting enzyme and Proteinase, kidney brush border neutral such as omapatrilat;

3) substrate of NO-synthase is like the L-l-arginine;

4) cholesterol reducing agent, like Statins (like atorvastatin/Lipitor ^TM) and shellfish special type (fibrates);

5) estrogenic agents and/or estrogen agonist and/or estrogen antagonist; Raloxifene or Lasofoxifene ((-)-suitable-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5 preferably; 6,7,8-naphthane-2-alcohol; And pharmaceutically acceptable salt, its preparation such as WO96/21656 are said);

6) PDE suppressor factor; More preferably PDE2,3,4,5,7 or 8 suppressor factor; Be preferably PDE2 or PDE5 suppressor factor and PDE5 suppressor factor (vide infra) most preferably, said suppressor factor preferably anti-each enzyme IC50 less than 100nM (condition be only topical or through being used to treat male erectile dysfunction to penis injection PDE3 and 4 suppressor factor);

7) vasoactive Erepsin (VIP), VIP stand-in, VIP analogue; More preferably by one or more VIP receptor subtypes VPAC1, VPAC or PACAP (PACAP); One or more VIP receptor stimulants or VIP analogue (like Ro-125-1553) or VIP fragment; One or more alpha-2-adrenoceptor antagonists and VIP combination (like Invicorp (Invicorp), aviptadil (Aviptadil)) mediation;

8) 5-hydroxytryptamine receptor agonist, antagonist or regulator; More preferably for agonist, antagonist or the regulator of 5HT1A (comprising VML670 [WO02/074288] and Flibaserin [US2003/0104980]), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 acceptor, comprise described in WO-09902159, WO-00002550 and/or the WO-00028993 those;

9) testosterone substitutes reagent (comprising the dehydrogenation androstanedione), testosterone (like Tostrelle ^TM, LibiGel ^TM), dihydrotestosterone or testosterone implant (implant);

10) SARM is like LGD-2226;

11) oestrogenic hormon, oestrogenic hormon and medroxyprogesterone or medroxyprogesterone acetate (MPA) are (promptly; As combination), or oestrogenic hormon and the agent of methyltestosterone hormone replacement therapy (as HRT especially premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, must U.S. element, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, tibolone);

12) for the regulator of the transportation of sympathin, Dopamine HCL and/or serotonin, like Wellbutrin, GW-320659;

13) for the receptor stimulant or the regulator of oxytocin/vassopressin, be preferably selectivity oxytocin agonist or regulator;

14), be preferably D3 or D4 selective agonist or regulator, like Apomorphine for the agonist or the regulator of Dopamine Receptors; With

15 Bendectin, for example 5-HT ₃Antagonist or neurokinine-1 (NK-1) antagonist.

The 5-HT that is fit to ₃Antagonist includes but not limited to granisetron, ondansetron, tropisetron, ranimustine, palonsetron, indisetron, dolasetron, Lotronex and azasetron.

Suitable NK-1 antagonist comprises; But be not restricted to; A Rui smooth (Aprepitant), casopitant, ezlopitant (ezlopitant), cilapitant, how appropriate smooth (netupitant), vestipitant, vofopitant (vofopitant) and 2-(R)-(1-(R)-3; 5-two (trifluoromethyl) phenyl) oxyethyl group-4-(5-(dimethylamino) methyl isophthalic acid, 2,3-triazole-4-yl) methyl-3-(S)-(4-fluorophenyl) morpholine.See for example International Patent Application Publication No. WO2006/049933.

For the handicapped purposes of compounds for treating lower urinary tract of the present invention, can include, but are not limited to especially with other combination of agents

● muscarinic acetylcholine receptor antagonist, for example tolterodine;

● alpha-2-adrenoceptor antagonists, particularly α 1 adrenoceptor antagonists or α 2 adrenoceptor antagonists;

● alpha adrenergic receptor agonist or partial agonist, particularly α 1 adrenoceptor agonists or partial agonist, or α 2 adrenoceptor agonists or partial agonist;

● 5HT2C agonist (seeing WO2004/096196);

● serotonin and NRI (SNRI);

Norepinephrine reuptake inhibitor (NRI), VESTRA for example, racemize or (S, S)-enantiomeric form;

● capsaicin receptor (VR) antagonist, for example capsaicine;

● alpha 2 delta ligands, for example gabapentin or lyrica;

● β 3-adrenoceptor agonists;

● 5HT1a receptor antagonist or 5HT1a receptor inverse agonists;

● prostanoid receptor antagonist, for example EP1 receptor antagonist.

About the purposes of formula (I) compound in treatment obesity and relative disease, compound also can use with other antiadipositas drugs combinations.Suitable antiadipositas drug comprises cannaboid 1 (CB-1) receptor antagonist (for example SR141716A), apo-B secretion/MTP (apo-B/MTP) suppressor factor (particularly intestines (gut) selectivity MTP suppressor factor, for example edipatapide or dirlotapide), 11 beta-hydroxy steroid dehydrogenase types-1 (1 type, 11 β-HSD) suppressor factor, peptide YY _3-36With its analogue, cholecystokinin-A (CCK-A) agonist, monoamine reuptake inhibitors (for example sibutramine), parasympathomimetic agent, β 3 adrenoceptor agonists, dopamine-receptor stimulant (for example bromocriptine), melanocyte-stimulation hormone receptor analogue, 5HT2c receptor stimulant, melanin-concentrating hormone antagonist, leptin (OB albumen), leptin analogue, leptin receptor agonist, galanin antagonist, lipase inhibitor (for example tetrahydrochysene Li Putading, i.e. orlistat (orlistat)), fenisorex (for example bombesin agonist), neuropeptide-Y receptor antagonist (particularly NPY-5 receptor antagonist), thyromimetic, dehydroepiandrosterone or its analogue, glucocorticoid receptor agonist or antagonist, aricine (orexin) receptor antagonist, type glucagon peptide-1 receptor stimulant, ciliary neurotrophic factor (Axokine for example ^TMAvailable from Regeneron Pharmaceuticals; Inc., Tarrytown, NY and Procter &Gamble Company; Cincinnati, OH), wild grey GAP-associated protein GAP (AGRP) suppressor factor of people, Ge Ruilin receptor antagonist, histamine 3 receptor antagonists or inverse agonist, neuromedin U receptor stimulant etc.Other antiadipositas drugs comprise the preferred agents of hereinafter, to those skilled in the art be well-known or this paper openly the back conspicuous.Compound of the present invention also can reduce the compound combination medicine-feeding of blood plasma cholesterol level with having of natural generation.The compound of this natural generation is commonly referred to dietetic product, and comprises for example Bulbus Allii extract, Hoodia plant milk extract and nicotinic acid.Preferred especially antiadipositas drug is selected from the CB-1 antagonist, intestines (gut) are selected MTP suppressor factor, orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY _3-36With its analogue and pseudoephedrine.Preferably, compound of the present invention and the combined therapy that is used to treat fat and the associated conditions administration that combines with the diet of exercise and science.Preferred CB-1 antagonist comprises USP 5,624, the SR141716A (SR141716A, the trade(brand)name Acomplia that describe in 941 ^TM, Sanofi-Synthelabo is on sale); With USP 5,747, the compound of describing in 524,6,432,984 and 6,518,264; The open US2004/0092520 of USP, US2004/0157839, US2004/0214855 and US2004/0214838; The U.S. Patent Application Serial 10/971599 that on October 22nd, 2004 submitted to; With the open WO02/076949 of PCT patent, WO03/075660, WO04/048317, WO04/013120 and WO04/012671.Preferred intestines selectivity MTP suppressor factor comprises USP 6,720, the dirlotapide that describes in 351; USP 5,521,186 and 5; 4-(4-(4-(4-((2-((4-methyl-4H-1,2 described in 929,075; 4-triazole-3-base sulfenyl) methyl)-2-(4-chloro-phenyl-)-1; 3-dioxolane (dioxolan)-4-yl) phenyl piperazine-1-yl phenyl methoxyl group))))-and 2-sec.-butyl-2H-1,2,4-triazole-3 (4H)-ketone (R103757); With USP 6,265, the implitapide of describing in 431 (BAY13-9952).Other representational antiadipositas drugs that in combination, pharmaceutical composition and the inventive method, use can use the known method preparation of those of ordinary skills, for example; Can be according to USP 4,929, the method for describing in 629 prepares sibutramine; Can be according to USP 3,752, the method for describing in 814 and 3,752,888 prepares bromocriptine; Can be according to USP 5,274, the method for describing in 143,5,420,305,5,540,917 and 5,643,874 prepares orlistat; Can according to the U.S. disclose 2002/0141985 with WO03/027637 in the method described prepare PYY _3-36(comprising analogue).

The one of preferred of this paper is the combination of compound of the present invention and one or more other treatment medicines, and said other treatment medicine is selected from: the PDE5 suppressor factor; Nep inhibitor; D3 or D4 selective agonist or regulator; Estrogenic agents and/or estrogen agonist and/or estrogen antagonist; Testosterone substitutes medicine, testosterone or testosterone and implants (implant); Oestrogenic hormon, oestrogenic hormon and medroxyprogesterone or medroxyprogesterone acetate (MPA) or oestrogenic hormon and methyltestosterone hormone replacement therapy medicine.

The preferably combination that is used to treat MED is the combination of compound of the present invention and one or more PDE5 suppressor factor and/or nep inhibitor.

The preferably combination that is used to treat FSD is compound of the present invention and PDE5 suppressor factor and/or nep inhibitor and/or D3 or D4 selective agonist or regulator and/or estrogenic agents, estrogen agonist, estrogen antagonist and/or testosterone alternative medicine, testosterone, testosterone is implanted and/or the combination of oestrogenic hormon, oestrogenic hormon and medroxyprogesterone or medroxyprogesterone acetate (MPA), oestrogenic hormon and methyltestosterone hormone replacement therapy medicine.

The preferred especially PDE5 suppressor factor that is used to treat the combination product of MED or FSD is 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones (Virga is especially as Citrate trianion);

(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351 or Tadalafil(Cialis));

2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil); 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azetidinyl (azetidinyl))-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl]-pyrimidine-5-methane amide (carboxamide) is (TA-1790) for N-(pyrimidine-2-base methyl); 3-(1-methyl-7-oxo-3-propyl group-6,7-dihydro-1 h-pyrazole be [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxy-benzsulfamide (DA8159) and its pharmaceutically acceptable salt.

The preferred especially nep inhibitor that is used for treating the combination product of MED or FSD is the compound that WO02/079143 explains.

The compound that is comprised in patent and the patented claim that this paper cross reference can be used according to the invention, we refer to the therapeutical active compound of definition in the claim (particularly claim 1) and concrete instance (all are all quoted as a reference).

If the combination of administration active medicine, so they can be simultaneously, separately or sequentially with identical or different preparation administration.

Biological experiment

Melanocortin-4 receptor agonists is active; Selectivity

Compound is renderd a service (EC to the excitement of 1 type and 3 type melanocortin receptors (MC1 and MC3) ₅₀ ) body Outer mensuration.

Agonist causes the activation of adenylate cyclase in the cell to the activation of melanocortin (MC) acceptor, adenylate cyclase enzymic synthesis second messenger signaling molecule 3 ', 5 '-encircle single adenosine phosphate (cAMP).Mensuration is handled change and the MC1 and the MC3 effect evaluation (EC of cAMP level behind reorganization MC1 and the MC3 cell strain with detection compound ₅₀) calculate as follows:

Use the standard molecular biology method,, set up the stable transfected cells strain with the full-length cDNA stable transfection human embryo kidney (HEK) or the Chinese hamster ovary cell strain respectively of coding human MC1 or MC3 acceptor.Detection compound is dissolved in the DMSO 99.8MIN. (DMSO) with 4mM.11 thirty log unit increment dilution series detection compound, begin from 50uM usually, detection compound is diluted in the damping fluid that comprises phosphate buffer salt (PBS), 2.5%DMSO and 0.05% Pluronic (pluronic) F-127 tensio-active agent.Collect the cell of the fresh culture of 80%-90% fusion, and resuspended in the Eagle ' s substratum (DMEM) of Dulbecco ' s improvement.(for MC3,10,000 cells, for MC1,20,000 cells) is added in the detection compound dilution series liquid in the 384 hole measurement plates with cell, and hatches 1 hour at 37 ℃.Use beta-galactosidase enzymes fragment complementation method afterwards, use Discoverx cAMP II test kit, measure cAMP concentration relative in every hole available from Britain GE Healthcare/Amersham Biosciences.Under the MC1 situation, DMEM comprises 3-isobutyl--1-methyl yellow purine (IBMX) of 750 μ M when re-suspended cell is used to test.The fluorescence reading of each experimental port converts the peaked effect percentage ratio that stimulates the corresponding control wells of hormone concentration with respect to the α melanocyte of maximum effect into.Use the SIGHTS of conventional software, with log ₁₀Inhibition concentration pairing effect percentage ratio carries out the curve fit of S type, confirms as EC through the detection compound concentration that software is half the with the effect between the S type dose response curve experimental point from low to high ₅₀Each experiment comprises that the α melanocyte stimulates the EC of hormone ₅₀Confirm that the α melanocyte stimulates hormone to use as standard substance, with the consistence of chase experiment, makes the EC that in different experiments, obtains ₅₀Relatively fair between the value.

The EC that confirms MC5 and MC4 through experimental technique D among the US2005/0176772 (28-30 page or leaf) and E respectively ₅₀Active.

At the Nle4 of MC4 acceptor, D-Phe7-α-MSH suppresses

Nle4, D-Phe7-α-MSH are the stable analogs of melanocyte-stimulation hormone (MSH), are the agonists of MC4 acceptor (MC4R).Use with [ ¹²⁵I] Nle4, the combination competitive assay that D-Phe7-α-MSH compares, but assessing compound suppresses Nle4, and D-Phe7-α-MSH is bonded to the ability of the film of the cell of expressing MC4R.

The cell of MC4R is expressed in homogenate, and through differential centrifugation separatory membrane fragment.CHO-CRE MC4R cytolemma and the coupling of A type PVT-PEI-WGA SPA pearl 2 hours, centrifugal 5 minutes of 1000RPM is suspended to 300ug pearl/ml (0.15ug film, 15ug pearl/hole).At TV is every hole 50 μ l damping fluid (25mM HEPES, 1mM MgCl ₂, 2.5mM CaCl ₂, 1% Pluronic F68,1 complete EDTA proteinase inhibitor sheet/50ml pH7) in, pearl/film mixture and 0.06nM [ ¹²⁵I] Nle4, the competitor part of D-Phe7-α-MSH and 11 semilog concentration is hatched, and is duplicate.SHU9119 through adding 100nM measures non-specific binding.Begin reaction through adding pearl/film, and orifice plate uses afterwards Wallac plate telltale to measure the amount of the radioactivity that occurs in incubated at room 12 hours (placing on the orifice plate vibrator in first hour).Use suitable software to confirm the Ki value through data analysis.

Preferably, compound of the present invention shows the binding constant at the MC4 acceptor, uses Nle4; The Ki value representation of D-Phe7-α-MSH; Be lower than about 1000nM, or more preferably be lower than 500nM, but more preferably be lower than about 100nM; And more preferably be lower than about 50nM, wherein use above-mentioned experiment to confirm said Ki value.

At the Nle4 of MC3 acceptor, D-Phe7-α-MSH suppresses

Nle4, D-Phe7-α-MSH are the stable analogs of melanocyte-stimulation hormone (MSH), are the agonists of MC3 (MC3R) acceptor.Use with [ ¹²⁵I] Nle4, the combination competitive assay that D-Phe7-α-MSH compares, but assessing compound suppresses Nle4, and D-Phe7-α-MSH is bonded to the ability of the film of expressing the MC3R cell.

The cell of MC3R is expressed in homogenate, and through differential centrifugation separatory membrane fragment.CHO-CRE MC3R cytolemma and the coupling of A type PVT-PEI-WGA SPA pearl 2 hours, centrifugal 5 minutes of 1000RPM is suspended to whole experimental concentration 800ug pearl/ml (1.2ug film, 40ug pearl/hole).At TV is every hole 50 μ l damping fluid (25mM HEPES, 1mM MgCl ₂, 2.5mM CaCl ₂, 1%Pluronic F68,1 complete EDTA proteinase inhibitor sheet/50ml pH7) in, pearl/film mixture and 0.06nM [ ¹²⁵] Nle4, the competitor part of D-Phe7-α-MSH and 11 semilog concentration is hatched, and is duplicate.Confirm non-specific binding through adding 100nM SHU9119.Begin reaction through adding pearl/film, and orifice plate uses afterwards Wallac plate telltale to confirm the amount of the radioactivity of appearance in incubated at room 12 hours (first hour places on the orifice plate vibrator).Use suitable software to confirm the Ki value through data analysis.

The screening of high-density drug drug interaction (DDI) 3 μ M cocktail

Drug interaction is the situation that material influences another kind of pharmaceutical activity, and promptly effect increases or reduces, or two kinds of medicines produce the new effect that two kinds of medicines do not produce together.Various processes can cause drug interaction, but relative commonly a kind of medicine influences the pharmacokinetics of another kind of medicine through the Cytochrome P450 that suppresses the another kind of medicine of metabolism.Because the importance of this phenomenon, think that the measurement in the DDI potentiality of the early stage new chemical entities of drug discovery process (NCEs) is important.

The DDI cocktail screening of carrying out full-automatic mode in people's hepatomicrosome (HLM), and the purpose of screening is for new chemical entities (NCE is provided; Detect at 3 μ M) to the single point assay of the DDI potentiality of 4 kinds of important cytochrome P 450 enzymes 1A2,2D6,2C9 and 3A4.

To substrate cocktail method end user's hepatomicrosome and the hypotype-specificity clinical medicine probe of P450DDI, and allow in single hatching measuring in the active inhibition of P4501A2,2D6,2C9 and 3A4.It carries out with high-throughput and detects metabolite through LC-MS/MS simultaneously.Use n-compound fully to detect and estimate this method.The probe substrate of using sees the following form.

The microsome source	People's hepatomicrosome of collecting,
		Microsome concentration	0.1mg/mL
P450 concentration	0.03μM
		Regeneration system rapidly	NADPH(1.3mM)
Experimental period	8 minutes

Probe substrate (enzyme of probe mark)	Concentration
		Tacrine (1A2)	2μM
Diclofenac (2C9)	5μM
		Dextromethorphane Hbr (2D6)	5μM
Midazolam (3A4)	2μM

Suppressor factor	Concentration
		NCE (detection compound)	3μM
Miconazole (general contrast)	3μM

When the NCE (detection compound/suppressor factor) of 3 μ M concentration exists and do not exist, measure the appearance of the metabolite of every kind of substrate in time.Measure the inhibition ability of compound,, and use figure below explanation as percent value.These data combine other to measure the suitability with evaluation NCEs afterwards, and help the design and the progress of compound.

% suppresses	IC50
		>;75％	<1μM
25-75％	1-10μM
		<25％	>;10μM

AGRP suppresses

Agouti GAP-associated protein GAP (AGRP) is endogenous antagonist/inverse agonist (people such as Lu, 1994, the Nature371:799-802 of MC4 acceptor high-affinity; People such as Ollman, 1997, Science278:135-138).(Mizuno Mobbs1999, Endocrinology.140:4551-4557), to suppress AGRP bonded ability be crucial through acting on the MC4 acceptor therefore to measure the obesity medicine to raise the AGRP level through fasting.The C-terminal fragment of at present having confirmed AGRP comprises MC4R and combines determiner (people such as Yang, 1999, Mol Endocrinol13:148-155), therefore use contrast [ ¹²⁵I] AGRP (87-132) but competition combine the experiment assessing compound to suppress AGRP and the membrane-bound ability of expressing the MC4R cell.For this reason, the cell of MC4R is expressed in homogenate, and through differential centrifugation separatory membrane fragment.At TV is every hole 100 μ l damping fluid (25mM HEPES, 1mM MgCl ₂, 2.5mMCaCl ₂, 0.5%BSA pH7.0) in, CHO-CRE MC4R cytolemma (12 μ g albumen) and 0.3nM [ ¹²⁵I] the competitor part of AGRP (87-132) and 11 semilog concentration hatches, and is duplicate.SHU9119 through adding 1 μ M confirms non-specific binding.Begin reaction through blooming, and orifice plate was incubated at room 2 hours.Use the vacuum collection device to filter termination reaction fast, use the ice-cold cleaning buffer solution of 200 μ l (the binding buffer liquid that contains 500mM NaCl) to clean subsequently 5 times through going up at GF/C filter paper (in 1%PEI, soaking in advance).Filter paper is immersed in the scintillation solution of 50 μ l, confirms the radioactive amount that occurs through liquid scintillation counting(LSC).Use suitable software to confirm the Ki value through data analysis.

Preferably, compound of the present invention shows the binding constant at the MC4 acceptor, uses the Ki value representation to AGRP; Ki is lower than about 1000nM, or more preferably is lower than 500nM, yet more preferably is lower than about 100nM; And more preferably be lower than about 50nM, wherein use above-mentioned experiment to confirm said Ki value.Use this experiment, compound according to the present invention shows the binding constant at the MC4 acceptor, uses the Ki value representation to AGRP, and Ki is lower than about 1000nM.

Food intake research:In order to estimate the MC4 agonist to the food intake of male rat in 24 hours and the influence of body weight.

In research beginning two weeks of precontract, the single cage of rat is raised, and convert light is according to regulating (9.30am-9.30pm).In research preceding 24 hours, rat adaptive technique laboratory apparatus ^*(Techincal ScientificEquipment) be cage (TSE).In morning research day, rat is assigned randomly to treatment group (n=5/ treatment) by body weight.Before light-off, every oral MC4 agonist or solvent accepted of rat.After the administration, rat is put back to the TSE cage immediately, and research whole process in (24 hours) monitoring rat food intake and water consumption.With beam broken form monitoring motor behavior.

When research finishes, sacrificed by exsanguination rat under the isoflurane anesthesia.Through heart puncturing extracting blood and be used for the drug concentration level and the analysis of biological label.

Data represent with mean SEM, and with the comparison between ANOVA analysis of control and the treatment group.< 0.05 thinks to have significance,statistical to p.

External metabolic rate is confirmed (people's hepatomicrosome (HLM); Rat liver microsomes (RLM) experiment)

Many medicines are by the metabolism of FscP system.Find that this kind of enzyme concentration in liver is high, and combine with the liver cell endoplasmic reticulum.Can obtain the enzyme system of half purified state through the segmental preparation of hepatomicrosome.Confirm that the vitro half-lives of compound in this system provides the indication of useful metabolic stability.

Material and reagent

All reagent are ANALAR levels.

1.200mM phosphate buffered saline buffer (Sigma)-the be dissolved in 100ml1M phosphate buffered saline buffer pH7.4 of 400ml MilliQ water.If desired, regulate pH to 7.4 with dense ortho-phosphoric acid, preparation in every month is also preserved (2-8 ℃) in refrigerator.

2.0.1M MgCl ₂.6H ₂O (BDH)-2.032g is dissolved in the 100ml MilliQ water, and in refrigerator, preserves (2-8 ℃).

3.0.02M NADP (Sigma)-15.3mg is dissolved in the 1000 μ l MilliQ water-and in refrigerator, to preserve (2-8 ℃) then subsequent use.

4.0.1M D-L isocitric acid (Sigma)-129mg is dissolved in the 5ml MilliQ water-and in refrigerator, to preserve (2-8 ℃) then subsequent use.

5. isocitric enzyme, IV type (Sigma)-in refrigerator, preserve (2-8 ℃).

6. substrate is preserved in refrigerator (2-8 ℃) in the mixable organic solvent storage liquid (about 1mg/ml) in methyl alcohol, ethanol or the water for example.

7.50mM p-Nitromethoxybenzene (PNA) (Aldrich)-7.65mg is dissolved in the 1ml methyl alcohol, and it is subsequent use in refrigerator, to preserve (2-8 ℃).

8.50 μ M p-NP (PNP) (Sigma)-0.69mg is dissolved in the 100ml water and in refrigerator, preserves (2-8 ℃).

9.20% trichoroacetic acid(TCA) (TCA) (BDH)-20g is dissolved in the 100ml MilliQ water, in the amber glass vessel, prepare, and in room temperature storage.

(note) 10.10M sodium hydroxide (BDH)-40g is dissolved in the 100ml MilliQ water, (safebreak) prepare in the glassware at " non-friable " because this exothermic heat of reaction should be practised when preparing this solution, and in room temperature storage.

11. liver or Supermix microsome ,-80 ℃ of storages, dissolving at once before use remains on ice and distribution (dispense).

12.MilliQ water.

13. the thermostatically controlled shaking water bath be set be about 37 ℃ and hatch.

14. the reagent (being generally organic solvent, acid or alkali) that termination is hatched.

The methodology of using liver and the MC external metabolic rate of Supermix to confirm

What following method was used for 1.5ml always hatches volume.

1. in testing tube, prepare following mixture:

Reagent	Storing solution concentration	Hatch concentration	Add volume (for the 1.5ml Incubating Solution)
				Phosphate buffered saline buffer pH7.4	200mM	50mM	375μl
MgCl ₂	0.1M	5mM	75μl
				Isocitric acid	0.1M	5mM	75μl
Isocitric enzyme	On bottle	1 unit/ml ^*	As follows ^*

^*For the new isocitric enzyme of each batch, calculate this volume

For example, protein concn=18mg/ml

Enzymic activity=3.3 units/mg

Therefore, activity specific=3.3x18 unit/ml=59 unit/ml

For the Incubating Solution of 1.5ml, need

2. melt microsome in room temperature, and add the microsome of q.s, obtaining final concentration is 0.5nmol Cytochrome P450/ml Incubating Solution, and for example for the 1.5ml Incubating Solution, the microsome volume of adding is:

3. add the MilliQ water of q.s, obtaining total Incubating Solution volume is 1.425ml.

4. take out the mixtures incubated of 237.5 μ l, and place detector tube as the PNA positive control.The PNA solution that adds 2.5 μ l mixes (whirlimix), and pipe is placed the support of thermostatically controlled shaking water bath.

5. take out 100 μ l and contrast, and be dispensed in the detector tube as no substrate.Detector tube is placed the support of thermostatically controlled shaking water bath.

6. add substrate to Incubating Solution.The substrate initial concentration should be 1 μ M.At remaining 1.162.5ml Incubating Solution) in the calculating of the substrate volume that needs following:

Notice that the volume of organic solvent of adding should be no more than 0.1% of Incubating Solution TV.

7. take out 100 μ l mixtures incubated and put into detector tube, as no cofactor contrast (no cofactorcontrol).Mix (Whirlimix) and place the support of thermostatically controlled shaking water bath.

8. preincubate contains pipe, the positive control of Incubating Solution mixture and did not have the cofactor control tube 5 minutes in being set to 37 ℃ thermostatically controlled shaking water bath.

9. add NADP initial action (add 75 μ l to every 1.162.5ml Incubating Solution mixture, the heliotropism control tube adds 12.5 μ l, and adds 5 μ l to no substrate pipe), and get first time point immediately.PNA positive control, no cofactor contrast and do not have the substrate pipe and hatch by total incubation time.

10. 9 different sampling spots of from 0 to 60 minute (common 0,3,5,10,15,20,30,45 and 60min) take out 100 μ l equal portions and termination reactions.Can use longer incubation time, but after 120 minutes, the microsome sex change.Can be through adding organic solvent, acid or alkali termination reaction.After hatching end of processing, no cofactor is used similarity method with no substrate contrast, and promptly identical reagent stops.

11. PNA positive control operation steps:

After final sampling, take out positive control, and add 1ml20%TCA to this pipe.Also preparation contains the pipe of the 50 μ M PNP standard substance of 250 μ l, and adds 1ml20%TCA.Mix (Whirlimix) two pipes, and kept about 5 minutes, make albumen precipitation.

Two pipes in being set to the instrument of 3500rpm centrifugal about 5 minutes.Take out the supernatant of 1ml, and place clean detector tube, remove nubbin.

Upwards reset and add NaOH, mix (Whirlimix), and keep mixing about 5 minutes into 1ml10M.Blank spectrophotometric is measured the absorbancy of PNP standard substance contrast zero(ppm) water afterwards in respect of zero(ppm) water at 400nm.Microsome 4-Nitroanisole O-demethylase is active to be calculated as follows:

The result calculates

The activity value of Incubating Solution must equate with 85% of the MV of effective Incubating Solution batch or be bigger.If do not meet this standard, must repeat so to hatch.

11. through experimental analysis sample (comprising the contrast of no cofactor (no cofactor) and no substrate), to confirm to eliminate kinetics to substrate specificity.

Data analysis

The data of using the aforesaid operations step to obtain can be quantitative according to the external intrinsic clearance (Clint) of substrate.Suppose that concentration of substrate is lower than Km, metabolism should be a first order kinetics, obtains the log-linearity curve that substrate is eliminated in time.

Can measure natural logarithm (1n) curve of time and fit the line of best fit of these data through drawing relative concentration of substrate (for example, medicine/interior reference example), confirm the substrate vitro half-lives.The slope of this line is the first order rate constant (k) that substrate is eliminated, and confirms through regression analysis.This rate constant can convert the transformation period into according to following equality:

Perhaps, rate constant can convert intrinsic clearance (Clint) into according to following equality:

Clint (μ l/min/mg)=(protein concn in the k/ Incubating Solution (mg/ml)) ^*1000

Preferably, compound of the present invention shows removing, confirms like above-mentioned experiment; Be somebody's turn to do with the clearance rate value representation, value is lower than about 200 μ L/min/mg, more preferably is lower than about 100 μ L/min/mg; Yet more preferably be lower than about 50 μ L/min/mg, and more preferably be lower than about 20 μ L/min/mg.Use this experiment, the clearance rate that detects according to compound of the present invention is lower than 200 μ L/min/mg.

Medication

Expection can crystallization or amorphous products administration as the compound of the present invention of drug use.Can obtain for example solid suppository, powder or film through the for example method of deposition, crystallization, lyophilize, spraying drying or evaporation drying.Can use microwave or radio-frequency seasoning to realize this purpose.

One or more compounds of the present invention can be independent, or combination, or with the array configuration administration of one or more other medicines (or as any its compsn).Usually, can with the dosage form administration of the acceptable vehicle of one or more pharmacy (excipient) combination.Term used herein " vehicle " is to describe any composition except that The compounds of this invention.The range of choice of vehicle is big, depends on the influence to solvability and stability of the special pattern, auxiliary material of for example administration, and the factors such as character of formulation.

The pharmaceutical composition of sending and its preparation method that are suitable for compound of the present invention are conspicuous to those skilled in the art.These compsns and its preparation method are visible, for example Remington ' s Pharmaceutical Sciences, the 19th edition (Mack publishing company, 1995).

Therefore the invention provides pharmaceutical composition, said pharmaceutical composition comprises compound and the pharmacy acceptable diluent or the carrier of formula (I).

Can use any suitable route of administration, be used for to Mammals, particularly the people provides the effective dose of The compounds of this invention.For example, can use oral (comprising oral cavity and sublingual administration), rectum, part, parenteral, eye usefulness, lung, nasal administration etc.Dosage form comprises tablet, lozenge, dispersion agent, suspensoid, solution, capsule, emulsion, ointment, aerosol etc.Preferably, the oral or intranasal administration of compound of formula (I).

The effective dose of the activeconstituents that uses can change according to the severity of the special compound that uses, mode of administration, mammiferous characteristic (for example, body weight), the state of an illness of being treated of being treated and the state of an illness of being treated.These dosage can easily be confirmed by those skilled in the art.

For the therapeutic dysfunction, give the of the present invention compound of dosage range, preferably from about 0.001 milligram (mg) to about 1000mg; From about 0.001mg to about 500mg, more preferably from about 0.001mg to about 100mg, even more preferably; From about 0.001mg to about 50mg; And especially, from about 0.002mg to about 25mg per kilogram of body weight, preferably with single oral dose or nose spray delivery.For example, oral administration need every day total dose from about 0.1mg to about 1000mg, and vein dosage only need be from about 0.001mg about 100mg extremely.But every day total dose single or broken dose administration, and can follow the doctor's advice, to exceed the general dosage range administration that this paper provides.

Combine mellitus and/or hyperglycemia when treatment is fat, or when only fat, usually when the every day of compound administration of the present invention dosage from about 0.0001mg extremely during about 1000mg; Preferably about 0.001mg is during to about 500mg; More preferably about 0.005mg is during to about 100mg, and special about 0.005mg about 50mg per kilogram the weight of animals extremely, preferably with single dose or broken dose 2 to 6 times on the one; Or during the sustained release forms form administration, can obtain gratifying result.Under 70kg adult's situation, every day, total dose was usually from about 0.7mg to about 3500mg.This dosage regimen of adjustable, thus best therapeutic response is provided.

When treatment mellitus and/or hyperglycemia; In the time of can using disease or the illness of formula I compound with other; When the every day of compound administration of the present invention, dosage was from about 0.001mg to about 100mg per kilogram the weight of animals; Preferably with single dose or broken dose 2 to 6 times on the one, or during the sustained release forms form administration, can obtain gratifying result.Under 70kg adult's situation, every day, total dose was usually from about 0.07mg to about 350mg.This dosage regimen of adjustable, thus best therapeutic response is provided.

These dosage are according to the people experimenter of the about 65kg to 70kg of mean body weight.For the experimenter who exceeds this scope, for example baby, the elderly and obese people, the doctor can easily confirm their dosage.

Compound Orally-administrable of the present invention.Oral administration can comprise to be swallowed, so that compound gets into gi tract, and/or oral cavity, tongue or sublingual administration, get into blood flow thereby make between the compound from mouth.

The formulation that is suitable for oral administration comprises solid, half-solid and liquid system, for example tablet; Comprise many or nanometer-particulate is soft or hard capsule, liquid or powder; Lozenge (comprising filling liq); Masticatory; Gelifying agent; Fast-dispersing amount form; Film; Vaginal jellies; Spraying; And oral cavity/mucous membrane sheet.

Liquid dosage form comprises suspensoid, solution, syrup and elixir.These formulations can be used as soft or hard capsule (for example; From the preparation of gelatin or HYDROXY PROPYL METHYLCELLULOSE) weighting material use, and generally comprise carrier, for example water, ethanol, polyoxyethylene glycol, Ucar 35, methylcellulose gum; Or suitable oil and one or more emulsifying agents and/or suspending agent.Liquid dosage form also can be through solid reconstruct preparation, for example from wafer.

Compound of the present invention also can use in dissolving, the rapidly disintegrating dosage form fast, Liang and Chen (2001) Expert Opinion in Therapeutic Patents for example, 11(6), the formulation described in the 981-986.

For Tabules, according to dosage, medicine can be formed the 1wt% to 80wt% of formulation, more common 5wt% to 60wt% from formulation.Except medicine, tablet comprises disintegrating agent usually.The instance of disintegrating agent comprises sodium starch glycolate, Xylo-Mucine, ECG-505, Sodium Croscarmellose, cross-linked polyvinylpyrrolidone, Vinylpyrrolidone polymer, methylcellulose gum, Microcrystalline Cellulose, the substituted hydroxy propyl cellulose of low alkyl group, starch, pregelatinized Starch and sodium-alginate.Usually disintegrating agent is formulation 1wt% to 25wt%, preferably from the 5wt% to 20wt% of formulation.

Usually use tackiness agent to influence the bond property of Tabules.Suitable binder comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetical glue, Vinylpyrrolidone polymer, pregelatinized Starch, hydroxy propyl cellulose and HYDROXY PROPYL METHYLCELLULOSE.Tablet also can comprise thinner, for example lactose (monohydrate, spraying drying hydrate, anhydrous form etc.), N.F,USP MANNITOL, Xylitol, Vadex, sucrose, sorbyl alcohol, Microcrystalline Cellulose, starch and Bibasic Calcium Phosphate duohydrate.

Tablet also comprises tensio-active agent alternatively, for example for example silicon-dioxide and talcum powder of lauryl sulfate sodium and polysorbate 80 and glidant.When existing, tensio-active agent can be tablet from 0.2wt% to 5wt%, and glidant can be tablet from 0.2wt% to 1wt%.

Tablet also comprises lubricant usually, for example Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate, and the mixture of Magnesium Stearate and sodium lauryl sulphate.Lubricant is generally the 0.25wt% to 10wt% of tablet, preferably from the 0.5wt% to 3wt% of tablet.

Other possible composition comprises inhibitor, tinting material, seasonings, sanitas and taste masked agent.

The tablet of example includes up to about 80% medicine, and to about 90wt%, thinner is from about 0wt% to about 85wt% from about 10wt% for tackiness agent, disintegrating agent from about 2wt% extremely about 10wt% and lubricant from about 0.25wt% about 10wt% extremely.

Tablet mixture can direct compression or through roller (roller) compressing tablet to form tablet.The part of tablet mixture or mixture can wet method, dry method or melt granulation, fusion condense or compressing tablet before extrude.Final preparation can comprise one or more layers, and can dressing or dressing not; Even can be wrapped in capsule.

The preparation of tablet is shown in Pharmaceutical Dosage Forms:Tablets, Vol.1, H.Lieberman and L Lachman (Marcel Dekker, New York, 1980).

The oral film that consumes that is used for people or beast is generally flexible water-soluble or hydroexpansivity thin-film dosage form; It can dissolve rapidly or mucosal adhesive, and said film comprises formula I compound, film-forming polymer, tackiness agent, solvent, wetting agent, softening agent, stablizer or emulsifying agent, viscosity-regulator and solvent usually.Some compositions of said preparation can have multiple function.

The compound of formula I can be for water miscible or water-insoluble.Water-soluble cpds comprises 1 weight % to 80 weight % usually, more is typically the solute of 20 weight % to 50 weight %.The relatively poor compound of solubleness can account for the more ratio of compsn, common 88 weight % up to solute.Perhaps, formula I compound can be the form of many particles pearl.

Film-forming polymer can be selected from natural polysaccharide, protein, or the synthetic hydro-colloid, and proportional range is 0.01 to 99 weight % usually, more is typically 30 to 80 weight %.

Other possible composition comprises inhibitor, tinting material, correctives and smell activator, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), lubricant, weighting agent, anti-pore forming material, tensio-active agent and taste masked agent.

Usually form through the thin water-based film that evaporation drying is coated with on upholder of removing the peel or paper according to film of the present invention.This can carry out in loft drier or pipe, is generally the spreader moisture eliminator of combination, or through freeze-drying or vacuum-drying.

The solid preparation that is used for oral administration can be formulated as quick-release and/or sustained release preparation.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.

For the sustained release preparation such as the USP 6,106 that are fit to of the object of the invention, described in 864.The release tech that is fit to is seen dried like the detailed description of high energy dispersion and infiltration and coated granule Pharmaceutical Technology On-line, 25 (2), 1-14, people such as Verma (2001).Use such as WO00/35298 for the Chewing gum of realizing sustained release are said.

Compound liquid of the present invention can directly be administered in blood, muscle or the intracorporeal organ.The mode that is fit to of parenteral admin comprises in vein, artery, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, in the encephalic, intramuscular, synovial membrane and subcutaneous administration.The equipment that is fit to for parenteral admin comprises pin (comprising micro-needle) syringe, needleless injector and infusion techniques.

Parenteral formulation is generally the aqueous solution, and it can contain vehicle, like salt; Glucide and buffer reagent are (preferably; PH is 3 to 9), still, for some application; They can be formulated as aseptic aqueous solution or dried forms to be used in combination with the solvent (as aseptic, pyrogen-free water) that is fit to with being more suitable for.

The preparation of the parenteral formulation under the aseptic condition (for example, through lyophilize) can be used and well known to a person skilled in the art standard drug technology Rapid Realization.

The solubleness of the compound of used formula (I) can increase through using the preparation technique that is fit in the parenteral aqueous preparation, as passing through to add the reagent that increases solubleness.

Preparation for parenteral admin can be formulated as quick-release and/or sustained release preparation.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.Therefore, compound of the present invention can be formulated as suspensoid or solid, semisolid, or the thixotropic fluid administration, as the implantation bank that the slowly-releasing active compound is provided.These examples of formulations comprise medicine-dressing support (stents) and comprise the semisolid and the suspensoid that gather (dl-lactic acid-common hydroxyethanoic acid) acid (PGLA) microballoon of carrying medicament.

Compound of the present invention can topical, skin (interior) administration or percutaneous dosing to skin or mucous membrane.The typical formulation of this purpose comprises gel, hydrogel, lotion, solution, emulsion, ointment, face powder, dressing, foam, film, transdermal patches, thin slice, implant, sponge, fiber, bandage and micro emulsion.Also can use liposome.Common carrier comprises alcohol, water, MO, whiteruss, white paraffin, glycerine, polyoxyethylene glycol and Ucar 35.Can add penetration enhancers-referring to, for example, J PharmSci, 88(10), 955-958, Finnin and Morgan (in October, 1999).

The alternate manner of topical comprises through electroporation, iontophoresis, ultrasonicly penetrates, phonophoresis and micro-needle or needleless (Powderject for example ^TM, Bioject ^TMDeng) injection.

The preparation of topical can be formulated as quick-release and/or sustained release preparation.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.

Compound of the present invention also can nasal administration or through inhalation, usually since the dry powdered form of self-desiccation powder inhalator (separately, as mixture, for example with the drying composite of lactose; Or, for example mix with phosphatide such as phosphatidylcholine as the mixing element particle), or as the sprays from pressurizing vessel, pump, injector, atomizer (preferably, using electrohydrodynamics to produce the atomizer of particulate mist); Or use or do not use the spraying gun that is fit to propelling agent, and said propelling agent is as 1,1, and 1; 2-Tetrafluoroethane or 1,1,1,2; 3,3, the 3-HFC-227, or as the nose drops.For using in the nose, powder can comprise bioadhesive polymer, for example, and chitosan or Schardinger dextrins.

Pressurizing vessel, pump, injector, atomizer or spraying gun; The solution or the suspension that comprise The compounds of this invention; It comprises ethanol for example, aqueous ethanol or other reagent that is used to disperse, dissolve or prolong active agent release that is fit to, as the propelling agent and the option list surface-active agent of solvent, like sorbitan trioleate, oleic acid or lactic acid oligomer.

Before dried powder or suspension formulation use, the pharmaceutical product micronization is formed the size (usually less than 5 microns) that is fit to through the suction delivery.This can realize through any suitable breaking method, as spiral spray grind, fluidised-bed spray grinds, to form supercritical fluid processes, high-pressure homogenization or the spraying drying of nano particle.

Capsule (for example; Make by gelatin or HYDROXY PROPYL METHYLCELLULOSE); Can be formulated as the powdered mixture that contains The compounds of this invention for bubble that in sucker or insufflator, uses (blisters) and cartridge case; The powder matrix such as lactose or starch and performance modifier such as l-leucine, N.F,USP MANNITOL or the Magnesium Stearate that are fit to.Lactose can be anhydrous or the monohydrate form, the preferred latter.Other vehicle that is fit to comprises Expex, glucose, SANMALT-S, sorbyl alcohol, Xylitol, fructose, sucrose and trehalose.

The aqueous preparation that is fit to that in the atomizer that uses electrohydrodynamics with generation particulate mist, uses can contain the The compounds of this invention of 1 μ g to 20mg in each braking, and each arresting volume can be 1 μ l to 100 μ l.General preparation can comprise compound, Ucar 35, sterilized water, ethanol and the sodium-chlor of formula (I).Other solvent that can replace Ucar 35 to use comprises glycerine and polyoxyethylene glycol.

The correctives that is fit to like TK-10 and l-Menthol, or sweeting agent, like asccharin or soluble saccharin, can add to the present invention and is used for sucking/those preparations of intranasal administration.

Use for example PGLA, the preparation of suction/intranasal administration can be formulated as quick-release and/or sustained release preparation.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.

In dried powder inhalation and the aerocolloidal situation, the valve of the amount (metered amount) through sending metering is confirmed dosage device (unit).Usually be set at the dosage of administration metering or contain " spraying (puff) " of the compound of 0.001mg to 10mg formula (I) according to position, unit of the present invention.Total per daily dose usually will be in 0.001mg to 40mg scope, and it can single dose administration, or more common in one day the dosed administration to separate.

Compound of the present invention can rectum or vagina administration, for example with suppository, pessary or enema forms.Theobroma oil is traditional suppository base, but optionally can use multiple other matrix.

The preparation of rectum/vagina administration can be formulated as quick-release and/or sustained release preparation.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.

Compound of the present invention also can be directly to eye or ear administration, usually with waits, the form of the drops of micronization suspensoid in the Sterile Saline of adjustable pH or solution.Other suitable eye usefulness and ear comprise ointment, gelifying agent, biodegradable (as absorbing the gel sponge with the preparation of administration; Collagen) and not biodegradable (like silicone) implant, thin slice, lens and particle or cryptomere system, like class ester vesica (niosomes) or liposome.Can be with polymkeric substance; Like cross linked polyacrylate, Z 150PH, mucinase, cellulose polymer compound (for example HYDROXY PROPYL METHYLCELLULOSE, hydroxy ethyl cellulose or methylcellulose gum) or the mixed polysaccharide polymkeric substance (for example; Agaropectin) and sanitas, mix together like benzalkonium chloride.These preparations also can pass through iontophoretic delivery.

Eye usefulness/ear can be formulated as quick-release and/or sustained release preparation with the preparation of administration.Sustained release preparation comprise delay-, continue-, pulse-, control-, target and procedural release.

Compound of the present invention can or contain the combination of polymers of polyoxyethylene glycol with water-soluble macromolecule entity (like Schardinger dextrins) and the verivate that is fit to thereof, and is being used for the solubleness of above-mentioned any administering mode, dissolution rate, taste masked, bioavailability and/or stability to improve them.

Find the drug-cyclodextrin mixture, for example, be generally used for most of formulations and route of administration.Can use and comprise and the non-mixture that comprises.Except directly and medicine compound, Schardinger dextrins also can be used as supplementary additive, promptly as carrier, thinner or solubility promoter.For these purposes the most frequently used be α-, β-and γ-Huan Hujing, their instance is shown in international patent application no WO91/11172, WO94/02518 and WO98/55148.

Because for example; Be used to treat the combination of the purpose administration active compound of specified disease or illness; Therefore comprise two kinds or multiple medicines compositions (at least a contain with good grounds The compounds of this invention) more in the scope of the present invention, they can be easily with the form combination of the test kit that is fit to the said compsn of co-administered.

Therefore, test kit of the present invention comprises two kinds or other pharmaceutical composition of more branches (at least a with good grounds formula of the present invention (I) compound that contains) and is respectively applied for the instrument of preserving said compsn, like container, the bottle that separates or the paper tinsel bag that separates.The instance of these test kits is and is used to wrap up used similar Blister Packages (blister pack) such as tablet, capsule.

Test kit of the present invention especially is fit to administration different dosage forms (for example, oral and parenteral), with various dose (separate) compsn of separating of administration at interval, or the compsn that is separated from each other of titration.Be auxiliary conformability, said test kit comprises administration usually and instructs, and can provide so-called memory auxiliary.

Others of the present invention are listed in claims.

Biological data

Embodiment number	MC4 ?EC50 (nM)	MC4 ?MSH ?Ki (nM)	MC3 ?EC50 (nM)	?MC3 ?MSH?Ki ?(nM)?	MC4 ?AgRP Ki (nM)	HLM ?(μL /min/ ?mg)	RLM ?(μL /min/mg)	Suppress at the metabolic % of the 3A4 of 3 μ M
									1	<0.52	43.9	39	<7.0	<8.5	54
2	4.53	27	4.26	124	59	<12.0	31	64
									3	11.9	16.4		<7.0	<19.8	60
4			55.9		51	60	74	38
									5	137	203	552	<7.0	27	34
6	18.9		1460		456		<8.5	32
									7	40	1600	714	21	11	19
8	27.5		1090		643	>;440	>;510	94
									9	39.3	520	523	240	411	68
10	11.9	276	493	977	223	20.5	42	19

11	111				417	14
									12	91.6					>;352	88.5
13	37.6		1020		106			6
									14	115		129			<9.0	<9.75
15	53.9		>;33400
									16	34.3		323		251	<45.5	<8.5	83
17	1.59	112	54.9	332	20	>;440	>;510	35
									18	55.5		>;8520		965	67	68	34
19	6.5	85.4	425	568	79	21	21	50
									20	16.4	251	1120	1020	253	31	51.5	35
21	2.81		283		66	144	58.5	25
									22	19.8		1050	5560	5960	179	96	54
23	4.75	65.7	185	264	79	<15.5	<8.5	35
									24	59.3		2510		>;955	355	>;510	87
25	12.4	10.9	189	<0.105	278	308	172	16
									26	22.5		4210		363	70	>;510	61
27	4.54		390		100	51	31	64
									28	24.4		938	1670	516	33	51	77
29	7.54				40	105	36	59
									30	5.77		61.5		112	141	69.5	38
31	22.9		410		526	188	292	60
									32	8.78	150	76.6	456	160	8	<8.5	31
33	13.4		193		220	186	72	19
									34	39.2				375	<7.0	<8.5	50
35	62.2		878		386	100	92	46
									36	168				1020	<7.0	17	59
37			325		422	19.5	23	45
									38	102				336	<7.0	<8.5	58
39			2100		751	95	58	30
									40	69.8		580		430	<7.0	<8.5	64

41	655	>;33300	3750	21	30	52
							42		>;20300		888	25	25	59
43	49.3	1590	248	37		44
							44	284	>;9630		2130			27
45	44.4	66.1	251	<7.0	<8.5	69
							46	15	50.8	?551	?134	<7.0	<8.5	74

Compare with solvent, the compound of the embodiment 2 of 3mg/kg and 10mg/kg is illustrated among Fig. 1 and 2 to 24 hours the ingestion of food of accumulating influence with to the effect that 24 hours body weight changes.

The present invention describes through following non-limiting example, wherein uses following abbreviation and definition:

APCI atmospheric pressure chemical ionization massspectrum

[α] _DThe specific rotation at 589nm place

Br is wide

filtermedium

The δ chemical shift

The d doublet

Two doublets of dd

The EI electro-spray ionization

Ex embodiment

The LRMS Low Resolution Mass Spectra

The m multiplet

The m/z mass spectra peak

The NMR nucleus magnetic resonance

The Prec precursor

The Prep preparation

The psi pound per square inch

The q quartet

S is unimodal

The t triplet

The tlc thin-layer chromatography

For synthetic convenient, simultaneously in many instances, compound by initially-separate, is converted into the corresponding hydrochloride that is used for the Analysis and Identification purpose with them with their free alkali form usually.For fear of uncertain factor, free alkali and HCl salt form all provide in this article.

For fear of ambiguity, compound used herein uses ACD Labs Name software v7.11 ^TMName.

Embodiment

Embodiment 1

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-two Methyl piperidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-3-cyanopyridine (nicotinonitrile)

(96mg 0.69mmol) joins that (200mg, 0.46mmol) (0.32mL is 1.8mmol) in the solution in acetonitrile (10mL), and mixture heated overnight under 70 ℃ of nitrogen with the N-ethyl diisopropyl amine from preparation 10 tetramethyleneimine with 2-chloro-5-cyanopyridine.Remove solvent in the vacuum, and resistates use methylene dichloride through column chromatography (silica gel) purifying, increase polarity to the dichloromethane solution wash-out that contains 5% methyl alcohol obtains title compound (191mg, 77%), is white solid. ¹H NMR (CD ₃OD, 400MHz) δ 0.4-0.6 (6H, 4x d), 0.78-0.82,1.60-1.68 and 1.97-2.05 (2H, 3x m); 2.73-2.80 (1H, m), 3.00-3.20 (1H, m), 3.68-4.37 (8H, m); 6.62 (1H, m), 7.01-7.08 and 7.37-7.48 (5H, 2x m), 7.74 (1H, m); 7.80 with 7.95 (1H, 2x dd), 8.40 (1H, m), 8.57 and 8.60 (1H, 2x d); LRMS (EI ⁺) 534 [MH ⁺]; [α] _D ²⁵=-47.0 (c=0.215, MeOH).

Embodiment 2

6-[(3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-and 4-(4-fluorophenyl)-4-hydroxyl-3,5-two Methyl piperidine-1-yl] carbonyl } tetramethyleneimine-1-yl] pyridazine-3-nitrile

With 3-chloro-6-cyanic acid pyridazine (according to US3; 637; 691 preparations) (20mg 0.14mmol) joins that (40mg is 0.09mmol) with N-ethyl diisopropyl amine (0.06mL from preparation 10 tetramethyleneimine; 0.37mmol) in the solution in acetonitrile (10mL), mixture heated overnight under 70 ℃ of nitrogen then.Remove solvent in the vacuum, and resistates use methylene dichloride through column chromatography (silica gel) purifying, increase polarity to the dichloromethane solution wash-out that contains 5% methyl alcohol obtains title compound (41mg, 83%), is white solid. ¹HNMR (CD ₃OD, 400MHz) δ 0.4-0.6 (6H, 4x d), 0.78-0.85,1.60-1.69 and 1.97-2.10 (2H; 3x m), and 2.72-2.80 (1H, m), 3.00-3.23 (1H, m); 3.68-4.38 (8H, m), 6.99-7.08 and 7.38-7.50 (6H, 2x m), 7.70 (1H; D), 7.80 and 7.94 (1H, 2x dd), 8.58 and 8.61 (1H, 2x d); LRMS (EI ⁺) 535 [MH ⁺].

Embodiment 3

(3R, 4R, 5S)-1-{ [(3S, 4S)-1-(6-chlorine pyridazine-3-yl)-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] Carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol

1, the 6-dichloro-pyridazine (173mg, 1.2mmol) join from preparation 10 tetramethyleneimine (100mg, 0.23mmol) with the N-ethyl diisopropyl amine (0.16mL, 0.93mmol) in the solution in acetonitrile (5mL), mixture heated overnight under 70 ℃ of nitrogen then.Remove solvent in the vacuum, and resistates use methylene dichloride through column chromatography (silica gel) purifying, it is white solid that increase polarity to the dichloromethane solution wash-out that contains 5% methyl alcohol obtains title compound (52mg, 42%). ¹HNMR (CD ₃OD, 400MHz) δ 0.4-0.6 (6H, 4x d), 0.78-0.85,1.60-1.69 and 1.97-2.10 (2H; 3x m), and 2.72-2.80 (1H, m), 3.00-3.23 (1H, m); 3.68-4.38 (8H, m), 6.99-7.08 and 7.38-7.50 (6H, 2xm), 7.70 (1H; D), 7.80 and 7.94 (1H, 2x dd), 8.58 and 8.61 (1H, 2x d); LRMS (EI ⁺) 544 [MH ⁺].

Embodiment 4

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(6-methoxyl group pyridazine-3-yl) tetramethyleneimine -3-yl] carbonyl }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol

With sodium tert-butoxide (31mg, 0.32mmol), 3-chloro-6-methoxyl group pyridazine (34mg, 0.23mmol), three (dibenzalacetone (dibenzylideneacetone)) two palladiums (0) (8.5mg; 0.009mmol) and 2; 2 '-two (diphenylphosphino)-1,1 '-(11.5mg 0.0185mmol) joins from the tetramethyleneimine (100mg for preparing 10 dinaphthyl; 0.23mmol) in the solution in toluene (10mL), mixture heated overnight under 80 ℃ of nitrogen then.Remove solvent in the vacuum, and resistates is dissolved in the ETHYLE ACETATE (25mL), uses water washing, dry (MgSO4) and evaporation.Through chromatography (silica gel) purifying, use methylene dichloride, increase polarity to the dichloromethane solution wash-out that contains 5% methyl alcohol and obtain title compound (48mg, 40%), be yellow spumescence. ¹H?NMR(CD ₃OD，400MHz)δ0.4-0.62(d+t+t，6H)，0.86(m，1H)，1.65(m，1H)，1.93-2.08(br，1H)，2.75(m，1H)，3.17(t，1H)，3.74(m，3H)，3.95(s，3H)，3.96-4.21(m，3H)，4.32(d，1H)，6.98-7.1(m，5H)，7.38-7.48(m，2H)，7.79+7.48(2x?dd，1H)，8.56(d，1H)；LRMS(EI ⁺)540[MH ⁺].

Embodiment 5

(3R, 4R, 5S)-4-(4-chloro-phenyl-)-1-{ [(3S, 4S)-1-(6-chlorine pyridazine-3-yl)-4-(5-fluorine pyridine-2-yl) Tetramethyleneimine-3-yl] carbonyl }-3,5-lupetidine-4-alcohol

To (3R, 4R, 5S)-4-(4-chloro-phenyl-)-1-{ [(3S; 4S)-and 4-(5-fluorine pyridine-2-yl) tetramethyleneimine-3-yl] carbonyl }-3,5-lupetidine-4-alcohol is (through the identical method preparation used with the amine of preparation 10, from preparing 17 aldehyde and (3R; 4s, 5S)-4-(4-chloro-phenyl-)-3,5-lupetidine-4-alcohol (according to International Patent Application Publication No. WO2005/077935) is initial) (120mg; 0.28mmol) in the solution in DMSO 99.8MIN. (2mL), add 3,6-dichloro-pyridazine (98mg; 0.56mmol), triethylamine (0.12mL, 0.84mmol) and cesium fluoride (13mg, 0.084mmol).Mixture stirred 3 hours under 110 ℃ of nitrogen.Reaction mixture is splined on the SCX post then with methyl alcohol (5mL) dilution, to remove nonbasic substances and methyl-sulphoxide, uses the NH of 2M with methanol-eluted fractions then ₃Eluant solution alkaline product in methyl alcohol.Remove solvent in the vacuum and obtain title compound (74mg, 49%), be colourless glue. ¹H NMR (CD ₃OD, 400MHz) δ 0.44-0.60 (6H, 4x d), 0.95-1.02,1.64-1.73 and 1.94-2.09 (2H, 3x m); 2.69-2.79 (1H, m), 2.99-3.06 and 3.16-3.22 (1H, 2x m), 3.74-3.79 (3H, m); 4.01-4.24 (4H, m), 4.32-4.36 (1H, m), 7.02-7.07 (1H; M), and 7.29-7.70 (7H, m), 8.45-8.49 (1H, m); LRMS (EI+) 544 [MH+].

Embodiment 6

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl Base }-4-(5-fluorine pyridine-2-yl) tetramethyleneimine-1-yl] pyridazine-3 (2H)-ketone

Will (70mg, solution 0.13mmol) be dissolved in the acetate of the degassing, and stirring and refluxing is spent the night under nitrogen from the chlorine pyridazine of embodiment 5.Remove solvent in the vacuum, resistates is through column chromatography (silica gel) purifying, with methylene chloride/ammoniacal liquor 95/5/0.5 wash-out then.Obtain title compound, be beige solid (37mg, 55%). ¹H NMR (CD ₃OD, 400MHz) δ 0.43-0.59 (6H, 4x d), 0.94-1.03,1.64-1.73 and 1.93-2.03 (2H, 3x m), 2.65-2.78 (1H; M), 2.97-3.03 and 3.14-3.20 (1H, 2x m), 3.62-3.79 (3H, m), 3.86-4.17 (4H, m); 4.31-4.35 (1H, m), 6.88-6.91 (1H, m), 7.30-7.42 (5H, m); 7.47-7.57 (1H, m), 7.63-7.68 (1H, m), 8.44-8.48 (1H, m); LRMS (EI+) 526 [MH+].

Embodiment 7

6-[(3S, 4S)-3-{ [(3R, 4R, 5S)-and 4-(4-chloro-phenyl-)-4-hydroxyl-3,5-lupetidine-1-yl] carbonyl Base }-4-(5-fluorine pyridine-2-yl) tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone

To pyridazinone (30mg from embodiment 6; 0.057mmol) THF (0.07mL of adding 1M hexamethyl two silica-based sodium amides (sodium hexamethydisllazide) in the solution of N (2mL); 0.07mmol) solution and lithiumbromide (6mg, 0.07mmol).At room temperature stirred the mixture under the nitrogen 30 minutes, add then methyl-iodide (0.004mL, 0.07mmol), and mixture under nitrogen in stirring at room 2 hours.Remove solvent in the vacuum, and resistates is through column chromatography (silica gel) purifying, with methylene chloride/ammoniacal liquor 95/5/0.5 wash-out.Obtain title compound, be yellow solid. ¹H NMR (CD ₃OD, 400MHz) δ 0.44-0.59 (6H, 4x d), 0.94-1.03,1.64-1.73 and 1.95-2.04 (2H, 3x m), 2.68-2.78 (1H; M), 2.95-3.01 and 3.14-3.21 (1H, 2x m), 3.62-3.81 (6H, m), 3.87-4.17 (4H, m); 4.31-4.35 (1H, m), 6.87-6.90 (1H, m), 7.25-7.34 (4H, m), 7.38-7.42 (1H; M), and 7.48-7.58 (1H, m), 7.64-7.69 (1H, m), 8.44-8.48 (1H, m); LRMS (EI+) 540 [MH+].

Embodiment 8

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(5-fluorine pyridin-3-yl) tetramethyleneimine-3-yl] Carbonyl }-3,5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol

To (3R, 4R, 5S)-1-{ [(3S; 4S)-and 4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl }-3,5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol is (through the identical method preparation used with the amine of preparation 10, from (3R; 4s, 5S)-3,5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol (according to International Patent Application Publication No. WO2005/077935) is initial) (50mg; 0.12mmol) the solution of toluene (5mL) in, add the 3-bromine, 5-fluorine pyridine (25mg; 0.14mmol), three (dibenzalacetones), two palladiums (tris (dibenzylidineacetone) dipalladium) (4.4mg; 0.0048mmol), BINAP (6mg, 0.0096mmol) and sodium tert-butoxide (26mg, 0.27mmol).Mixture is stirred overnight under 80 ℃ of nitrogen.Remove solvent in the vacuum, and resistates with methylene chloride/ammoniacal liquor 99/1/0.1, increases polarity to 95/5/0.5 wash-out through column chromatography (silica gel) purifying.Obtain title compound (11mg, 18%), for yellow gluey. ¹H NMR (CD ₃OD, 400MHz) δ 0.33-0.53 (6H, 4x d), 0.81-0.93,1.81-1.92 and 2.08-2.28 (2H, 3x m); 2.69-2.78 (1H, m), 2.99-3.20 (1H, m), 3.61-3.94 (5H, m); 4.01-4.23 (2H, m), 4.34-4.42 (1H, m), 6.81-6.90 (1H, m); 7.26-7.50 (3H, m), 7.70-7.94 (4H, m), 8.51-8.62 (2H, m); LRMS (EI+) 510 [MH+].

Embodiment 9

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl)-1-pyridazine-3-base tetramethyleneimine-3-yl] carbonyl Base }-3,5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol

To (3R, 4R, 5S)-1-{ [(3S; 4S)-and 4-(5-chloropyridine-2-yl) tetramethyleneimine, the 3-yl] carbonyl }-3,5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol is (through the identical method preparation used with the amine of preparation 10; From (3R, 4s, 5S)-3; 5-dimethyl--4-pyridine-2-phenylpiperidines-4-alcohol (according to International Patent Application Publication No. WO2005/077935) is initial) (50mg, add in the solution of DMSO 0.12mmol) (2mL) 3-chlorine pyridazine (28mg, 0.24mmol), cesium fluoride (18mg; 0.12mmol) and triethylamine (0.05mL, 0.36mmol).Mixture is stirred overnight under 100 ℃ of nitrogen.Reaction mixture is with 10mL ETHYLE ACETATE dilution, and with the water washing of 3x20mL.The water extract that merges is used the 10mL ethyl acetate extraction, and the organic extract liquid that merges is used the 10mL brine wash, dry (MgSO ₄), remove solvent in the vacuum then.Resistates with methylene chloride/ammoniacal liquor 99/1/0.1, increases polarity to 95/5/0.5 wash-out through column chromatography (silica gel) purifying.Obtain title compound (16mg, 27%), for yellow gluey. ¹HNMR (CD ₃OD, 400MHz) δ .0.20-0.37 (6H, 4x d), 0.91-1.13,1.67-1.76 and 1.94-2.09 (2H, 3x m); 2.54-2.62 (1H, m), 2.87-2.93 and 2.99-3.05 (1H, 2x m), 3.61-3.74 (3H, m); 3.86-4.08 (4H, m), 4.20-4.26 (1H, m), 6.83-6.88 (1H, m); 7.11-7.44 (4H, m), 7.63-7.78 (2H, m), 8.30-8.46 (3H, m); LRMS (EI+) 493 [MH+].

Embodiment 10

6-1 (3S, 4S)-3-(5-chloropyridine-2-yl)-4-{ [(3R, 4R, 5S)-4-(5-chloropyridine-2-yl)-4-hydroxyl -3,5-lupetidine-1-yl] carbonyl } tetramethyleneimine-1-yl]-2-methyl pyridazine-3 (2H)-ketone

Always from preparing 15 carboxylic acid (42mg; 0.08mmol) the solution of methylene dichloride (3mL) in add N-ethyl diisopropyl amine (0.04mL; 0.25mmol), I-hydroxybenzotriazole (15mg; 0.095mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, mixture stirred 30 minutes under nitrogen then.Adding is from the amine of preparation 16, and mixture stirred overnight under nitrogen.Reaction mixture is used the washing of saturated NaHCO3 (20mL) and salt solution (20mL) then with methylene dichloride (20mL) dilution.Organic layer is through MgSO ₄Drying is filtered and evaporation obtains the yellow oily solid.Through column chromatography (silica gel) purifying, with methylene dichloride and the methylene chloride wash-out that increases polarity to 95/5, obtain title compound, be yellow solid (31mg, 67%). ¹H?NMR(CD ₃OD，400MHz)δ0.36-0.6(m，6H)，1.18(br，1H)，1.89(br，1H)，2.16(br，1H)，2.71(m，1H)，3.13(m，1H)，3.6-4.2(s+m，9H)，4.33(d，1H)，6.89(d，1H)，7.2-7.5(m，3H)，7.78-7.92(m，2H)，8.56(d，2H)；LRMS(EI ⁺)558[MH ⁺].

Embodiment 11-46

Embodiment 11-46 is according to the method preparation of above-mentioned for example 1-10, from the pyridine aldehydes that is fit to ¹With 4 that are fit to substituted 3,5-lupetidine-4-alcohol ²Initial.

1.2-methoxypyridine-5-formaldehyde is from commercially available.Other aldehyde is as preparing described in 2,17,18 and 22.

2. (3R, 4s, 5S)-and 4-(5-chloropyridine-2-yl)-3, described in 5-lupetidine-4-alcohol as the preparation 16.Synthesizing of other required piperidines alcohol is of International Patent Application Publication No. WO2005/077935.

Preparation

Preparation 1

5-chloro-2-iodine pyridine

(11.05mL, (20.0g, 0.103mol) in the solution in acetonitrile (120mL), (23.3g, 0.155mol), mixture heated (being equipped with drying tube) 3 hours under refluxing then to add Soiodin then 0.155mol) to join 2-bromo-5-chloropyridine with Acetyl Chloride 98Min..Be reflected in the ice bath and cool off,, use ETHYLE ACETATE (2x100mL) extraction then carefully with the alkalization of unsaturated carbonate aqueous solutions of potassium.The organic layer that merges washs with the saturated sodium sulfite aqueous solution (200mL), dry (MgSO ₄) and evaporation.Then resistates is being placed same reaction and treatment condition,, obtaining title compound (18.71g, 75%) then, be brown solid to guarantee complete reaction. ¹H?NMR(CDCl ₃，400MHz)δ7.30(1H，dd)，7.65(1H，d)，8.35(1H，d)；LRMS(APCI ⁺)240[MH ⁺]。

Preparation 2

5-chloropyridine-2-formaldehyde

Will (18.71g 78.1mmol) be dissolved in the THF (100mL), and under nitrogen, is cooled to-15 ℃ from preparation 2 iodide.(solution in 84.4mmol) guarantees that temperature keeps below 0 ℃ for 2M, 42.2mL in THF to drip isopropylmagnesium chloride then.Reaction mixture is cooled to-15 ℃, stirred 1 hour, and (9.0mL 116mmol), keeps temperature to be lower than 0 ℃ to drip N.Reaction mixture is warmed to room temperature, and stirs 1 hour, and then be cooled to 0 ℃, then through dripping HCl (100mL) cancellation carefully of 2M.After add accomplishing, at room temperature stirred the mixture 30 minutes, then through add saturated sodium bicarbonate aqueous solution with pH regulator to 6-7.Separate organic layer, and water layer extracts with methylene dichloride (2x200mL).The organic layer that merges is with water washing (200mL), drying (MgSO ₄), in rotatory evaporator, concentrate then, keep temperature less than 30 ℃, obtain crude product (13.7g), be brown oil, it just is not further purified and uses. ¹H?NMR(CDCl ₃，400MHz)δ7.35(1H，d)，7.95(1H，d)，8.73(1H，s)，10.02(1H，s)；LRMS(APCI ⁺)142[MH ⁺].

Preparation 3

(2E)-3-(5-chloropyridine-2-yl) tert-butyl acrylate

Under-78 ℃ of nitrogen; (2.5M is in hexane, and 34mL 85mmol) is added dropwise to diethyl phosphonyl tert.-butyl acetate (tert-butyl diethylphosphonoacetate) (19.1mL with n-Butyl Lithium; 81mmol) in the solution of ether (80mL), and continue to stir 30 minutes.Drip then from the solution of preparation 2 crude aldehyde (from the iodide of the 78.1mmol of preparation 1) in ether (20mL), keep temperature to be lower than-65 ℃.When adding completion, through 2 hours mixture is warmed to room temperature, then through adding the careful cancellation of saturated aqueous ammonium chloride (200mL).Mixture is with ether (2x150mL) extraction, and the organic extract liquid that merges washs dry (MgSO with salt solution (200mL) ₄) and evaporation.Resistates is used pentane through column chromatography (silica gel) purifying, increases polarity to pentane/ETHYLE ACETATE 8:2 wash-out and obtains title compound (13.34g, 74% through 2 steps), is oily matter. ¹H?NMR(CDCl ₃，400MHz)δ1.51，(9H，s)，6.79(1H，d)，7.35(1H，d)，7.52，(1H，d)，7.66(1H，dd)，8.55(1H，d)；LRMS(APCI ⁺)240[MH ⁺].

Preparation 4

(2E)-3-(5-chloropyridine-2-yl) vinylformic acid trifluoroacetate

With the drips of solution of trifluoroacetic acid (10mL) in methylene dichloride (10mL) add with ice-cooled from prepare 3 ester (2.09g, 8.7mmol) in the solution in methylene dichloride (10mL), gained mixture stirred overnight at room temperature then.Remove solvent in the vacuum, adding toluene (10mL) also removes in a vacuum, adds methylene dichloride (10mL) then and remove in a vacuum to obtain title compound (2.44g, 94%), is red solid. ¹H?NMR(CD ₃OD，400MHz)δ6.86(1H，d)，7.64(2H，m)，7.87(1H，dd)，8.59(1H，d)；LRMS(APCI ⁺)184[MH ⁺].

Preparation 5

(4S)-4-benzyl-3-[(2E)-and 3-(5-chloropyridine-2-yl) third-2-alkene acyl]-1,3-oxazolidine-2-ketone

Will (2.44g, THF 8.2mmol) (15mL) solution be cooled to-78 ℃ from preparation 4 acid under nitrogen.(2.85mL, 20mmol), (1.11mL, 9.0mmol), the speed that control adds makes temperature remain below-65 ℃ to drip trimethyl-acetyl chloride then to drip triethylamine.In-78 ℃ mixture was stirred 2 hours then.Will under-78 ℃ of nitrogen ⁿ(2.5M is in hexane, and 4.26mL 10.7mmol) is added dropwise to (4S)-4-benzyl-1, and (1.74g, 9.8mmol) in the solution in THF (15mL), the speed that control adds makes temperature remain below-65 ℃ to 3-oxazolidine-2-ketone for BuLi., through intubate the oxazolidone anion solutions is added in the mixed acid anhydride solution after 20 minutes-78 ℃ of stirrings in-78 ℃.In-78 ℃ of stirred reaction mixtures 20 minutes, slowly be warmed to ambient temperature overnight then.Reaction is through adding saturated aqueous ammonium chloride (30mL) cancellation, and vacuum concentration is to remove THF then.The solids filtered deposition obtains title compound (1.52g, 54%) with the ether washing, is light yellow solid.Evaporation ether washing lotion is to doing, and pulp in ether is filtered then and obtained further product (0.42g, 15%). ¹H?NMR(CDCl ₃，400MHz)δ2.84(1H，t)，3.37(1H，d)，4.22(2H，m)，4.78(1H，m)，7.2-7.4(5H，m)，7.51(1H，d)，7.69(1H，d)，7.86(1H，d)，8.23(1H，d)，8.62(1H，s)；LRMS(APCI ⁺)343[MH ⁺].

Preparation 6

(4S)-4-benzyl-3-{ [(3S, 4S)-1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl Base }-1,3-oxazolidine-2-ketone

With trifluoroacetic acid (90 μ L; 1.2mmol) join from preparation 5 De oxazolidone (1.93g; 5.6mmol) methylene dichloride (20mL) in suspension in, dripped through 10 minutes then N-benzyl-N-(methoxymethyl) trimethyl silyl amine (2.3mL, 9.0mmol).Add and accomplish afterreaction in stirred overnight at room temperature.Reaction mixture is handled with saturated sodium bicarbonate aqueous solution (20mL), separates each layer then.Water layer is with methylene dichloride (2x20mL) extraction, and the organic layer that the merges (MgSO that is dried ₄) and evaporation.Resistates, increases polarity to 2:3 wash-out and obtains unwanted (4S)-4-benzyl-3-{ [(3R with ETHYLE ACETATE/pentane 2:8 through column chromatography (silica gel) purifying; 4R)-1-benzyl-4-(5-chloropyridine; The 2-yl) tetramethyleneimine-3-yl] carbonyl }-1,3-oxazolidine-2-ketone (1.16g, 44%) is the first wash-out composition; (4S)-4-benzyl-3-{ [(3S with needs; 4S)-and 1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl }-1,3-oxazolidine-2-ketone (1.18g, 45%) is the second wash-out composition. ¹H?NMR(CDCl ₃，400MHz)δ2.75(2H，m)，2.92(1H，m)，3.20(3H，m)，3.27(1H，br)，3.68(2H，br)，4.14(2H，m)，4.23(1H，m)，4.50(1H，m)，4.67(1H，m)，7.10-7.40(11H，m)，7.58(1H，dd)，8.50(1H，d)；LRMS(APCI ⁺)476[MH ⁺].

Preparation 7

(3S, 4S)-1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-methyl-formiate

With sodium methylate (664mg, 12mmol) join from preparation 6 oxazolidone (1.17g, 2.5mmol) and methylcarbonate (1.03mL 12mmol) in the solution in methylene dichloride (15mL), reacts stirred overnight at room temperature then.Reaction mixture concentrates in a vacuum, and resistates is distributed between ETHYLE ACETATE (50mL) and water (30mL).The HCl of water layer through adding 2M (～6mL) neutralization, vacuum concentration then.Resistates grinds with acetonitrile (25mL), filters then.Concentrated filtrate obtains that (3S 4S)-1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-carboxylic acid (123mg, 16%), is yellow solid (for spectroscopy data referring to preparation 8).With the dry (MgSO of ethyl acetate layer ₄) and evaporation.Resistates, increases polarity to 2:3 wash-out and obtains title compound (371mg, 45%) with ETHYLE ACETATE/pentane 2:8 through column chromatography (silica gel) purifying, is colorless oil. ¹H?NMR(CDCl ₃，400MHz)δ2.71(1H，t)，2.97(1H，t)，3.05(2H，m)，3.23(1H，m)，3.63(5H，m)，3.82(1H，q)，7.15-7.35(6H，m)，7.55(1H，d)，8.46(1H，s)；LRMS(APCI ⁺)331[MH ⁺].

Preparation 8

(3S, 4S)-1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-carboxylic acid dihydrochloride

(135mg, water 3.3mmol) (5mL) solution join that (371mg 1.1mmol) in De diox (10mL) solution, at room temperature stirs the mixture then and spends the night from preparation 7 ester with NaOH.The vacuum concentration reaction mixture, in water-soluble (10mL) and with the HCl of 2M (～1.7mL) neutralize.Mixture concentrates in a vacuum then, grinds and filters with acetonitrile (20mL).Filtrating is with the HCl ethereal solution acidifying of 2M, and vacuum concentration obtains title compound (290mg, 68%) then, is solid. ¹H?NMR(CD ₃OD，400MHz)δ3.40-4.20(6H，m)，4.53(2H，m)，7.40-7.60(6H，m)，7.81(1H，d)，8.60(1H，br)；LRMS(APCI ⁺)317[MH ⁺].

Preparation 9

(3R, 4R, 5S)-1-{ [(3S, 4S)-1-benzyl-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl Base }-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol

With I-hydroxybenzotriazole (230mg, 1.7mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (354mg 1.8mmol) joins from preparation 8 acid (522mg; 1.5mmol) in methylene dichloride (10mL) and triethylamine (1.03mL; 7.4mmol) in solution in, at room temperature stirred the mixture then 30 minutes, add (3R then; 4s; 5S)-4-(4-fluorophenyl)-3,5-lupetidine-4-alcohol hydrochloride (according to the US2005/176772 preparation) (384mg, 1.5mmol).Stir the mixture under the room temperature and spend the night, remove solvent in the vacuum, and resistates distributes between ETHYLE ACETATE (50mL) and saturated sodium bicarbonate aqueous solution (50mL).Organic layer is with salt solution (50mL) washing, and dry (MgSO4) also evaporates.Resistates is used methylene dichloride through column chromatography (silica gel) purifying, increases polarity to the methylene dichloride wash-out that contains 5% methyl alcohol and obtains title compound (546mg, 71%), is oily matter. ¹H?NMR(CD ₃OD，400MHz)δ0.3-0.6(6H，4x?d)，1.23(1H，m)，1.75-1.95(2H，m)，2.72(1H，t)，2.85(1H，m)，2.90-3.20(3H，m)，3.45-4.05(5H，m)，4.32(1H，d)，7.02(3H，m)，7.20-7.50(7H，m)，7.80，(1H，dd)，8.50(1H，d)；LRMS(APCI ⁺)522[MH ⁺].

Preparation 10

(3R, 4R, 5S)-1-{ [(3S, 4S)-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-yl] carbonyl }-4-(4-fluorobenzene Base)-3,5-lupetidine-4-alcohol

(0.3mL 2.8mmol) joins that (370mg, 0.7mmol) (0.27mL is in methylene dichloride 1.6mmol) (10mL) solution, then with mixture reflux 3 hours with the N-ethyl diisopropyl amine from preparation 9 acid amides with 1-chloroethyl chloro-formic ester.Be cooled in the room temperature final vacuum and remove solvent, and resistates is distributed between 10% aqueous citric acid solution (30mL) and methylene dichloride (30mL).Organic layer water (30mL) washing, dry (MgSO ₄) and evaporation.The dark oily matter of gained is dissolved in the methyl alcohol (10mL), and reflux 3 hours.Remove solvent in the vacuum, resistates is through column chromatography (silica gel) purifying then, and with the solution of the methylene dichloride that contains 5% methyl alcohol, the eluant solution that increases polarity to the methylene dichloride that contains 10% methyl alcohol obtains title compound (305mg, 100%), is oily matter. ¹H NMR (CD ₃OD, 400MHz) δ 0.4-0.6 (6H, 4x d), 1.00-1.06,1.77-1.82 and 1.98-2.05 (2H; 3x m), and 2.76-2.82 (1H, m), 3.00-3.20 (2H, m); 3.40-4.10 (6H, m), 4.36 (1H, m) 7.00-7.50 (5H, m); 7.85 with 7.95 (1H, 2x dd), 8.61 and 8.63 (1H, 2x d); LRMS (APCI ⁺) 432 [MH ⁺].

Preparation 11

(3S, 4S)-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-methyl-formiate

(2.33mL 21.4mmol) joins that (1.77g, 5.35mmol) (2.1mL is 12mmol) in the solution in methylene dichloride (10mL), then with mixture reflux 3 hours with the N-ethyl diisopropyl amine from preparation 7 ester with chloroformic acid 1-chloro-ethyl ester.After being cooled to room temperature, remove solvent in the vacuum, and resistates is dissolved in the methyl alcohol (10mL), and reflux 16 hours.Remove solvent in the vacuum, resistates is used methylene dichloride through column chromatography (silica gel) purifying then, increases the mixture that polarity to the eluant solution of the methylene dichloride that contains 10% methyl alcohol obtains required product and N-ethyl diisopropyl amine, is oily matter.This oily matter is dissolved in the ETHYLE ACETATE (30mL), and filters the gained deposition.Filtrating concentrates in a vacuum, and resistates is dissolved in the acetonitrile (25mL).Filter the gained deposition and obtain title compound (619mg, 48%), be white solid. ¹H?NMR(CD ₃OD，400MHz)δ3.46(m，1H)，3.61-3.77(m，7H)，3.74(s，3H)，3.98(m，1H)，7.42(d.1H)，7.82(dd，1H)，8.57(d，1H)；LRMS(APCI ⁺)241[MH ⁺].

Preparation 12

(3S, 4S)-1-(6-chlorine pyridazine-3-yl)-4-(5-chloropyridine-2-yl) tetramethyleneimine-3-methyl-formiate

Always from prepare 11 tetramethyleneimine (350mg 1.50mmol) adds 3 in the solution in methyl-sulphoxide (10mL), the 6-dichloro-pyridazine (330mg, 2.20mmol), triethylamine (0.61mL, 4.40mmol) and cesium fluoride (220mg, 1.45mmol).Under 80 ℃ of nitrogen, stir the mixture and spend the night.Reaction mixture is dissolved in the 25mL ETHYLE ACETATE, and uses the 20mL water washing.Separate organic layer, and water layer extracts with 25mL ETHYLE ACETATE more again.The acetic acid ethyl acetate extract that merges is through MgSO ₄Drying is filtered and evaporation obtains greenish orange look oily solid, and it increases polarity to 95/5 methylene chloride wash-out through the column chromatography purifying with methylene dichloride.Obtain title compound, be yellow solid. ¹H?NMR(CD ₃OD，400MHz)δ3.66(s，1H)，3.72(m，1H)，3.78(t，1H)，3.96-4.12(m，4H)，7.04(d，1H)，7.42(m，2H)，7.79(d，1H)，8.52(s，1H)；LRMS(El ⁺)353[MH ⁺].

Preparation 13

(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(6-oxo-1,6-dihydrogen dazin-3-yl) tetramethyleneimine-3-formic acid Methyl esters

Will (803mg, 2.27mmol) solution be dissolved in the deoxidation acetate, and refluxed under nitrogen heating 44 hours from preparation 12 chlorine pyridazine.Remove solvent in the vacuum, and add 15mL methyl alcohol.Then HCl gas is fed in the reaction mixture up to saturated, then mixture stirred overnight under drying tube.Remove methyl alcohol in the vacuum, then resistates is assigned to DCM and 10%K ₂CO ₃Between.Separate organic layer, through MgSO ₄Drying is filtered and evaporation obtains title compound, is filbert solid (577mg, 76%). ¹H NMR (CD ₃OD, 400MHz) δ 3.58-3.76 and 3.83-3.97 (6H, 2x m), 3.65 (3H, s), 6.89 (1H, d), 7.31 (1H, d), 7.39 (1H, d), 7.79 (1H, dd), 8.52 (1H, d); LRMS (EI ⁺) 335 [MH ⁺].

Preparation 14

(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(1-methyl-6-oxo-1,6-dihydrogen dazin-3-yl) tetramethyleneimine -3-methyl-formiate

Always from preparing 13 pyridazinone (557mg; 1.66mmol) (1M is in THF to add hexamethl disilamine base sodium (hexamethydisilazide) in the solution in N (10mL); 2.00mL, 2.00mmol) and lithiumbromide (173mg, 2.00mmol).Be reflected under the nitrogen and stirred 10 minutes, add then methyl iodide (0.083mL, 1.30mmol).Be reflected under the nitrogen and stirred 4 hours, be assigned to then between ETHYLE ACETATE (30mL) and the water (30mL).Separate organic layer, dry through MgSO4, filtration and evaporation obtain brown oil, and it uses column chromatography (silica gel) purifying, uses 100% methylene dichloride, increases polarity to 95/5 methylene chloride wash-out.Obtain title compound, be yellow oil (500mg, 90%). ¹H?NMR(CD ₃OD，400MHz)δ3.64(m，9H)，3.92(m，3H)，6.87(d，1H)，7.26(d，1H)，7.37(d，1H)，7.79(dd，1H)，8.51(s，1H)；LRMS(EI ⁺)349[MH ⁺].

Preparation 15

(3S, 4S)-4-(5-chloropyridine-2-yl)-1-(1-methyl-6-oxo-1,6-dihydrogen dazin-3-yl) tetramethyleneimine -3-carboxylic acid

Always (500mg 1.43mmol) adds sodium hydroxide (172mg, 5mL aqueous solution 4.30mmol) in the solution in diox (10mL) from the ester 14 for preparing 14.Be reflected at stirred overnight under the drying tube.Remove solvent in the vacuum, resistates is water-soluble, with the HCl neutralization of 4 equivalent 2M, and evaporation.Resistates and 20mL acetonitrile stir, and filter then and obtain light yellow solid (512mg contains 3 equivalent NaCl-338mg product+174mg NaCl). ¹H?NMR(CD ₃OD，400MHz)δ3.6(m，2H)，3.64(s，3H)，3.7(t，1H)，3.9(m，3H)，6.88(d，1H)，7.27(d，1H)，7.41(d，1H)，7.79(dd，1H)，8.52(s，1H)；LRMS(EI ⁺)335[MH ⁺].

Preparation 16

(3R, 4s, 5S)-and 4-(5-chloropyridine-2-yl)-3,5-lupetidine-4-alcohol

Steps A: (3R, 4s, 5S)-and 4-(5-chloropyridine-2-yl)-1-(4-methoxy-benzyl)-3, the 5-lupetidine -4-alcohol

(6.0g, 31.2mmol) solution in toluene (90mL) is cooled to-78 ℃ with 2-bromo-5-chloropyridine under the nitrogen.Dripped n-Butyl Lithium (2.5M is in hexane) (15mL, 37.5mmol), and mixture stirred 1 hour in-78 ℃ through 12 minutes.Dripped (3R then through 10 minutes; 5S)-1-(4-methoxy-benzyl)-3; 5-lupetidine-4-ketone (according to International Patent Application Publication No. WO2005/077935 preparation) (6.93g; 28.1mmol) solution in toluene (15mL), and mixture is warmed to room temperature then in-78 ℃ of restir 3 hours.Mixture stirred 5 minutes through pouring saturated ammonium chloride (100mL) cancellation into then, and mixture is dispensed between water (50mL) and the ETHYLE ACETATE (300mL).Separate organic phase, and use ETHYLE ACETATE (2x300mL) apple water intaking phase again.Through the organic extract liquid that dried over mgso merges, filter and be evaporated to the dried rough midbody that obtains then.Through chromatography (silica gel) purifying; With the solution of 2% methyl alcohol in methylene dichloride, (10:1 methyl alcohol: 880 ammonia) eluant solution in methylene dichloride obtains (3R, 4s to increase polarity to 10%; 5S)-4-(5-chloropyridine-2-yl)-1-(4-methoxy-benzyl)-3; 5-lupetidine-4-alcohol is orange (8.48g, 83%).

Step B: (3R, 4s, 5S)-and 4-(5-chloropyridine-2-yl)-3,5-lupetidine-4-alcohol

Will (6.56g 18.2mmol) be dissolved in the anhydrous methylene chloride (100mL), and (2.02g 20.0mmol), and is cooled to 5 ℃ with solution under nitrogen to add triethylamine from the product of steps A.(3.1g 21.9mmol) drops in the solution of stirring, and at room temperature mixture is stirred 2.5 hours after adding completion again with chloroformic acid 1-chloroethene ester.Mixture is with 10% wet chemical (3x50mL) washing then, through dried over mgso and be evaporated to dried.Reflux and in methyl alcohol (100mL), rough oily matter was heated 2.5 hours down, remove solvent in the vacuum then.Resistates is dissolved in methylene dichloride (100mL) and the methyl alcohol (10mL), adds solid carbonic acid potassium (10g), and uneven mixture was stirred 30 minutes.Leach solid carbonic acid potassium, and evaporated filtrate is to doing.Then, crude product uses the dichloromethane solution that contains 10% methyl alcohol through column chromatography (silica gel) purifying, and (10:1 methyl alcohol: dichloromethane solution wash-out 880 ammonia) obtains title compound (3.37g, 77%), is little yellow solid to increase polarity to 20%. ¹H NMR (400MHz, CDCl ₃) δ 0.53 (3H, s), 0.57 (s, 3H), 2.60-2.71 (m, 2H), 3.13 (q, 2H), 3.32 (d, 2H), 7.43 (d, 1H), 7.78 (dd, 1H), 8.50 (1H, d), 9.58 (br, 1H), 9.84 (br, 1H); LRMS (APCI+) 241 and 243 [MH ⁺]

Preparation 17

5-fluorine pyridine-2-formaldehyde

Method according to preparation 1 and 2 prepares title compound, and is initial from 2-bromo-5-fluorine pyridine.Obtain containing the crude product of THF and ether, it just is not further purified and uses. ¹H?NMR(CDCl ₃，400MHz)δ7.57(1H，dt)，8.03(1H，dd)，8.62(1H，d)，10.04(1H，s)；LRMS(APCI ⁺)126[MH ⁺].

Preparation 18

6-formyl radical-3-cyanopyridine

With 6-methyl-3-cyanopyridine (10.0g; 84.6mmol) and iodine (20.0g, 78.8mmol) 20 minutes (the purifying reactor off-gas (reaction exhaust) to remove dimethyl sulphide with SYNTHETIC OPTICAL WHITNER) of heating under 150 ℃ of nitrogen of the mixture in methyl-sulphoxide (150mL).After being cooled to room temperature, carefully add saturated sodium bicarbonate aqueous solution (200mL), and the gained mixture extracts with toluene (3x100mL).The organic extract liquid that merges is used brine wash, dry (MgSO ₄) and evaporation obtain required product, be orange (5.65g, 50%) that it is not further purified just and uses. ¹H?NMR(CDCl ₃，400MHz)δ8.06(1H，d)，8.17(1H，dd)，9.05(1H，d)，10.12(1H，s).

Preparation 19

5-methoxyl group-2-picoline

(50.0g, (103g 1.83mol) in the suspension in methyl-sulphoxide (750mL), and stirs mixture 1.5 hours under room temperature nitrogen 6-picoline-3-alcohol 0.458mol) to join powder KOH.(30mL, 68.3g 0.481mol) dropped to (heat release) in the Vandyke brown mixture with methyl-iodide through 1 hour then.After at room temperature stirring 1.5 hours, add entry (1.0L), and mixture extracts with ETHYLE ACETATE (2x300mL).The organic extract liquid that merges is used brine wash, dry (MgSO ₄) and evaporate in rotatory evaporator in 40 ℃.Resistates use pentane through column chromatography (silica gel) purifying, and increase polarity to eluent ethyl acetate obtains volatile products, for ETHYLE ACETATE～1:1 mixture (40g ,～23.3g product, 41%) ¹H NMR (CDCl ₃, 400MHz) δ 2.45 (3H, s), 3.79 (3H, s), 7.02 (1H, d), 7.08 (1H, dd), 8.16 (1H, d).

Preparation 20

5-methoxyl group-2-picoline 1-oxide compound

Will between-(51.3g, 0.297mol) portioning joins preparation 19 compound (1:1 mixture 40g and ETHYLE ACETATE, 23.3g 189mmol) in the solution in methylene dichloride (1500mL), at room temperature stirred the mixture 2 hours the chlorine peroxybenzoic acid.Water (250mL) solution with S-WAT (45g) is added in the reaction then, and mixture was stirred 15 minutes, at this moment carries out starch/KI test paper for the existence of oxygenant and shows as negative result.Separate organic layer, through MgSO ₄Drying, and evaporation obtains faint yellow solid (54g), its be required product and-chloro-benzoic acid (mCBA)～the 1:1 mixture.It is not further purified and just carries out following step. ¹H?NMR(CDCl ₃，400MHz)δ3.84(3H，s)，6.97(1H，dd)，7.19(1H，d)，7.34(1H，t，mCBA)，7.48(1H，d，mCBA)，7.94(1H，d，mCBA)，8.04(1H，s，mCBA)，8.36(1H，d).

Preparation 21

(5-methoxypyridine-2-yl) methyl alcohol

With trifluoroacetic anhydride (28.2mL, 203mmol) be added dropwise to ice-cooled product from preparation 20 (～135mmol) in the solution in methylene dichloride (500mL), mixture is warmed to room temperature, and stirred overnight.The Tlc analysis revealed still has a large amount of starting substances, and (15mL 108mmol), and stirs mixture 27 hours more therefore to drip a trifluoroacetic anhydride again.Through careful adding methyl alcohol (250mL) cancellation reaction, and stirred 30 minutes, concentrate in a vacuum then.Carefully add 2.5M sodium hydroxide (100mL) then, and mixture extracts with methylene dichloride (4x100mL).Dry organic extract liquid (the MgSO that merges ₄), and evaporation obtains required product (12g, 64%), the starting material that this product is recovered (～15mol%) pollution. ¹H?NMR(CDCl ₃，400MHz)δ3.80(3H，s)，4.40(1H，br)，4.66(2H，s)，7.16(1H，dd)，7.20(1H，d)，8.17(1H，d).

Preparation 22

5-methoxypyridine-2-formaldehyde (carbaldehyde)

With MnO ₂(97.0g, 360mmol) portioning joins that (12g 86mmol) in the solution in methylene dichloride (500mL), at room temperature stirred the gained suspension 64 hours then from preparation 21 alcohol.Through

filter reaction mixture; And remove solvent in the vacuum and obtain the required product (8.6g of orange buttery; 73%), this product is polluted by 5-methoxyl group-2-picoline 1-oxide compound (15mol%).1HNMR(CDCl3，400MHz)δ3.93(3H，s)，7.26(1H，dd)，7.91(1H，d)，8.37(1H，d)，9.94(1H，s).

Claims

1. the compound of formula (I) or its pharmaceutically acceptable salt:

Wherein

One among X and the Y is N, and another is CH,

R ¹Be phenyl, 2-pyridyl, C ₃-C ₆Naphthenic base or CH ₂(C ₃-C ₆Naphthenic base), wherein said loop section is optional to be replaced by one or more substituting groups, and said substituting group is independently selected from F, Cl, CN, methyl and methoxyl group,

R ²Be H, F or Cl, condition is when Y is N, R ²Not F or Cl,

Het is the 6-unit ring that contains 1 or 2 N atom, and wherein this encircles and is aromatic nucleus, or in ring, contains 2 two keys and=O substituting group, and this ring is optional to be replaced by one or more substituting groups, and said substituting group is independently selected from F, Cl, OH, CN, methyl, ethyl, NH ₂, NHCH ₃, N (CH ₃) ₂And methoxyl group.

2. according to compound or its pharmaceutically acceptable salt of claim 1, wherein X is that N and Y are CH.

3. according to compound or its pharmaceutically acceptable salt of claim 1, wherein R is a chlorine.

4. according to each compound or its pharmaceutically acceptable salt in the claim 1,2 or 3, wherein

R ¹By the substituted phenyl of one or more substituting groups, said substituting group is independently selected from F, Cl, CN, methyl and methoxyl group for optional.

5. according to compound or its pharmaceutically acceptable salt, the wherein R of claim 4 ¹Be phenyl, 4-chloro-phenyl-or 4-fluorophenyl.

6. according to each compound or its pharmaceutically acceptable salt in the claim 1,2 or 3, wherein

R ¹Be C ₃-C ₆Naphthenic base.

7. according to compound or its pharmaceutically acceptable salt of claim 6, wherein

R ¹Be cyclopropyl or cyclohexyl.

8. according to each compound or its pharmaceutically acceptable salt, wherein R in the claim 1,2 and 3 ²Be H or F.

9. according to Claim 8 compound or its pharmaceutically acceptable salt, wherein R ²Be H.

10. according to each compound or its pharmaceutically acceptable salt in the claim 1,2 and 3, wherein

Het is pyridine-2-base, pyridin-3-yl, pyridazine-3-base, 6-oxo-1,6-dihydrogen dazin-3-base, 6-oxo-1,6-dihydropyridine-3-base, 2-oxo-1; 2-dihydro-pyrimidin-4-base, 6-oxo-1; 6-dihydro-pyrimidin-4-base, 2-oxo-1,2-dihydropyridine-4-base or 6-oxo-1,6-dihydropyridine-2-base; It is optional by one or more substituting groups replacements, and said substituting group is independently selected from F, Cl, OH, CN, methyl, ethyl and methoxyl group.

11. compound or its pharmaceutically acceptable salt according to claim 10; Wherein Het is pyridine-2-base, pyridin-3-yl, pyridazine-3-base or 6-oxo-1; 6-dihydrogen dazin-3-base; It is optional by one or more substituting groups replacements, and said substituting group is independently selected from OH, CN, F, methyl and methoxyl group.

12. according to compound or its pharmaceutically acceptable salt of claim 11, wherein Het is pyridine-2-base or pyridazine-3-base, each with respect to the contraposition of the key that partly links to each other with tetramethyleneimine by OH, CN or methoxyl group replacement.

13. according to compound or its pharmaceutically acceptable salt of claim 12, wherein Het is a pyridazine-3-base, its with respect to the contraposition of the key that partly links to each other with tetramethyleneimine by OH, CN or methoxyl group replacement.

14. according to the compound of claim 1, it is selected from:

Or its pharmaceutically acceptable salt.

15. according to the compound of claim 14, it is selected from:

Or its pharmaceutically acceptable salt.

16. according to the compound of claim 15, it is selected from:

Or its pharmaceutically acceptable salt.

17. pharmaceutical composition, it contains in the claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 or 16 each compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or adjuvant.

18. pharmaceutical composition, it contains described compound of claim 1 and thinner.

19. the pharmaceutical composition of each compound or its pharmaceutically acceptable salt or claim 17 or 18 is used for treating the purposes of the medicine of disease, illness or the state of an illness that the MC4 receptor activation is responded in the claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 or 16 in preparation.

20. according to the purposes of claim 19, wherein said disease is sexual dysfunction, obesity, mellitus or lower urinary tract dysfunction.