CN101516835A - Selective androgen receptor modulators, analogs and derivatives thereof and uses thereof - Google Patents

Selective androgen receptor modulators, analogs and derivatives thereof and uses thereof Download PDF

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CN101516835A
CN101516835A CN 200780034701 CN200780034701A CN101516835A CN 101516835 A CN101516835 A CN 101516835A CN 200780034701 CN200780034701 CN 200780034701 CN 200780034701 A CN200780034701 A CN 200780034701A CN 101516835 A CN101516835 A CN 101516835A
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J·T·多尔顿
D·D·米勒
I·拉科夫
C·博尔
M·L·莫勒
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Ohio State University Research Foundation
University of Tennessee Research Foundation
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Abstract

This invention provides new compounds and uses thereof in treating a variety of diseases or conditions in a subject, including,inter alia, prostate cancer, muscle wasting diseases and/or disorders or a bone-related diseases and/or disorders.

Description

SARM, their analogue and derivative and their purposes
The cross reference related application
The application requires the interests of U.S. Provisional Patent Application of submitting on July 19th, 2,006 60/831880 and the U.S. Provisional Patent Application of submitting on July 19th, 2,006 60/831988; These two applications are all incorporated herein by reference with it.
Invention field
The invention provides the nuclear hormone receptor binding compounds, comprise they composition and they in individual various diseases of treatment or the using method in the illness, described disease or illness especially comprise prostate cancer, muscular atrophy and the relevant therewith disease or the disease or the illness of illness and/or bone photo pass.
Background of invention
The nuclear hormone receptor superfamily is a maximum class transcription factor, relates to physiological process widely.48 members of this family are divided three classes, and the 1st class comprises the acceptor of male sex hormone (AR), oestrogenic hormon (ER-α and ER-β), glucocorticosteroid (GR), progesterone (PR) and mineralocorticoid (MR).The 2nd class comprises the acceptor of retinoid, Tiroidina and vitamins D, and the 3rd class comprises that its part has acceptor to be identified (orphan (orphans)).Nuclear hormone receptor has the N-terminal territory (NTD) of the rare sign of function, responsible acceptor combines the ligand binding domain (LBD) that territory (DBD), the hinge area that contains nuclear localization signal and binding partner also activated or suppressed function of receptors with DNA response element bonded DNA.And, there are two mobilizing function territories, one is arranged in NTD (AF-1), and another is arranged in LBD (AF-2).The I receptoroid is because amino acid sequence homology, the medium homology of LBD and similar secondary and the tertiary structure feature and the steroid part common chemical feature of DBD height often can combine (being cross reaction) with the part of other I receptoroid.For example, in early days to studies show that of AR and ER, steroid is contacted with spiral-3 residue by steroid A-ring and D-encircles and contacts with spiral-11 residue and location in LBD, may all be general to all steroid hormone receptors.
Androgen receptor (" AR ") is a part activated transcription regulatory protein, and it is by its inducing androgenic active male sexual development of mediation of endogenous and sexual function.Male sex hormone is commonly called male sex hormones.Male sex hormone is the steroid that is produced by testis and adrenal cortex in vivo, perhaps can synthesize in the laboratory.Androgenic steroids plays an important role in many physiological processs, comprise male sex character for example muscle and bone amount, prostate gland growth, spermatogeny and male hair pattern generation and keep (Matsumoto, Endocrinol.Met.Clin.N.Am.23:857-75 (1994)).Endogenous steroid male sex hormone comprises testosterone and Standone (" DHT ").Testosterone is the main steroid of testicular secretion, and is the main circulation male sex hormone of finding in the male blood plasma.In many peripheral tissues, testosterone is converted into DHT by 5.Therefore, DHT is considered to medium in the cell of most of androgenic effects people such as (, Molec.Endocrinol.9:208-18 (1995)) Zhou.Other steroid male sex hormone comprises the ester of testosterone, pentamethylene propionic ester (cypionate) for example, propionic ester, phenylpropionic acid ester (phenylpropionate), cyclopentanepropanoiacid acid ester (cyclopentylpropionate), dissident's acid esters (isocarporate), heptanoate and decylate, and other synthetic androgen, 7-methyl-nortestosterone (" MENT ") and acetic ester thereof (people such as Sundaram for example, " 7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen ForMale Contraception; " Ann.Med., 25:199-205 (1993) (" Sundaram ")).Because AR relates to male sexual development and sexual function, so AR may be a target of realizing the Hormone Replacement Therapy of male contraceptive or other form.
Human progesterone receptor (PR) exists three kinds of different hypotypes: PR-A, PR-B and PR-C (people such as Kastner, EMBO J 9:1603-1614,1990; People such as Wei, Mol Endo 10:1379-1387,1996), wherein, PR-A and PR-B are the abundantest.Yet the PR-A hypotype is non-constant in target tissue to the ratio of PR-B hypotype, and this can change cell response, because the activity of each hypotype can change.
Seldom there is compound under a variety of conditions, all to demonstrate the part progestin.RU-486, the most generally the antiprogestin of Shi Yonging only demonstrates partial agonist activity under selected condition.Antiprogestin compound with partial agonist activity is useful to the disease and the illness for the treatment of various progestogen adjustings, yet, these known antiprogestins seldom only have the limited portion agonist activity, and this area still needs to have the antiprogestin of partial agonist activity widely.
World population increases and the social consciousness of birth control has promoted a large amount of contraception research.In any case contraception all is the problem of a difficulty.It involves religion with the branding of culture and society, and the most for certain, it is with important health concerns.When the focus of this problem concentrated on male contraceptive, situation only can worsen.Although there is suitable contraception apparatus, in history, the social expectation women makes the decision of contraception and accepts the consequence.Though the worry to sexually transmitted disease (STD) makes the man recognize the sexual custom that need cultivate safety and be responsible for more, the women still often bears the main pressure of practising contraception and selecting.The womankind has some to select, from interim mechanism (for example sponge and Diaphragm contraceptive) to interim chemical process (for example spermaticide).The womankind also has some governable more persistent selections, and for example physical unit comprises intrauterine device and diaphragm, and more persistent chemical treatment, for example Contraceptive pill and subdermal implants.Yet so far, the only selection of menfolk comprises uses condom and vasotomy.Yet many men dislike using condom, because this can weakening property susceptibility, interference is spontaneous, and probably because of breaking or improper use causes pregnancy.Vasotomy also falls from favor.If there is the method for control fertility more easily to use for the man, particularly before sexual behaviour, need not the longer-lasting answers of warming-up exercise, these methods just can increase the possibility that the man bears more contraception responsibility significantly so.
The administration of male steroid (for example testosterone and derivative thereof) seems potential especially in this respect, because these compounds have the inhibition gonad-stimulating hormone of combination and replace androgenic character (people such as Steinberger, " Effect of Chronic Administration of Testosterone Enanthate on SpermProduction and Plasma Testosterone; Follicle Stimulating Hormone; andLuteinizing Hormone Levels:A Preliminary Evaluation of a Possible MaleContraceptive ", Fertility and Sterility 28:1320-28 (1977)).The testosterone of long term administration heavy dose stop the generation (no sperm) of sperm fully or with oligospermia to very low level (oligospermia).The degree that causes sterile required inhibition sperm to produce is not clear.Yet, one piece of nearest report of the World Health Organization shows, the intramuscularly Testoviron-Depot causes 98% the male sex who receives treatment not have sperm or serious oligospermia (be every milliliter less than 3,000,000 sperms) and sterile (World HealthOrganization Task Force on Methods And Regulation of Male Fertility weekly, " Contraceptive Efficacy of Testosterone-Induced Azoospermia and Oligospermiain Normal Men, " Fertility and Sterility 65:821-29 (1996)).
Developed multiple testosterone ester, they are absorbed slowlyer after intramuscularly, produce bigger male sex hormone effect thus.Testoviron-Depot is most popular in these ester classes.Although Testoviron-Depot is determining that hormone agents is used for aspect the feasibility of male contraceptive very big value being arranged, but it has several shortcomings, comprise the rational highest level (Wu of the excusing from death that to inject and after intramuscular injection, to occur immediately testosterone weekly, " Effects of Testosterone Enanthate in Normal Men:Experience From aMulticenter Contraceptive Efficacy Study, " Fertility and Sterility 65:626-36 (1996)).
Male and female bone mineral density (BMD) all reduces along with the age.Reducing of the amount that bone mineral content (BMC) and BMD reduce and bone strength is relevant, and the patient is fractured.
Osteoporosis is the general skeletal diseases, it is characterized in that the bone amount is few, osseous tissue is degenerated and cause bone fragility (bone fragility) and fracture susceptibility increases.In the U.S., this illness influence surpasses 0.25 hundred million population, causes every year to surpass 1,300,000 example fracture, comprises annual 500000 routine spinal fractures, 250,000 routine hip fractures, 240,000 routine fracture of the carpal bone.Hip fracture is the osteoporosis severest consequences, and wherein the patient of 5-20% is dead in 1 year, surpasses survivor's deformity of 50%.The old man suffers from the risk maximum of osteoporosis, therefore, along with aging population, estimates that this problem can significantly increase.In ensuing 60 years, global fracture incidence is estimated to increase by three times, and a research estimates that the year two thousand fifty will have 4,500,000 routine hip fractures in the world.
It is bigger than the male sex that the women suffers from the osteoporosis risk.In 5 years after climacteric, women's bone loss violent acceleration.The other factors that increases risk comprises the living habit of smoking, alcohol abuse, sitting and low calcium absorption.Yet osteoporosis also often betides on one's body the male sex.Very definite, the male sex's bone mineral density reduced along with the age.The reducing relevant and cause fracture easily of the reduction of bone mineral content and density and bone strength.The potential molecular mechanism of the pleiotropic effects of sexual hormoue in non-germinal tissue has only just begun to be familiar with by people, still, is clear that, plays an important role on the male sex hormone of physiological concentration and the oestrogenic hormon bone stable state in keeping whole life.Therefore, when male sex hormone and estrogen deprivation occurring, the result is that bone reconstruction speed increases, and this absorbs the balance tendency that absorbs and be shaped, and this causes the bone loss of general.The male sex, the reducing naturally of ripening stage sexual hormoue (androgenic direct minimizing and by androgenic periphery aromizing produce estrogenic low-level) relevant with the bone fragility.In the male sex of castration, also observed this effect.
Myatrophy is meant that the carrying out property of the carrying out property loss of muscle mass and/or muscle is weak and degenerates, and comprises the cardiac muscle and the unstriated muscle of the skeletal muscle of controls movement or voluntary muscle, control heart (myocardosis).Chronic myatrophy is with carrying out property loss, the muscle weakness of muscle mass and deteriorates to the chronic disease of feature.
The muscle mass loss that takes place in the myatrophy process can cause the degraded of mytolin to characterize by katabolism.The reason that protein catabolism takes place is high-speed singularly protein degradation, the protein synthesis of lower velocity or both combinations singularly.Be minimizing and the myatrophy that the protein degradation of high level or the mytolin katabolism that the protein synthesis of low degree causes all can cause muscle mass.
Myatrophy is relevant with chronic, neuropathic, genetic or communicable symptom, disease, illness or illness.They comprise muscular dystrophy, for example duchenne muscular dystrophy and myotonia atrophica; Myatrophy, for example myatrophy (PPMA) after the poliomyelitis; Emaciation, for example cardiogenic cachexia, acquired immune deficiency syndrome (AIDS) emaciation and cancer cachexia, malnutrition, leprosy, diabetes, nephropathy, chronic obstructive pulmonary disease (COPD), cancer, whole latter stage renal failure, Sarcopenia, pulmonary emphysema, osteomalacia, HIV infection, AIDS and myocardosis.
In addition, other situation is also relevant with myatrophy with illness also can cause myatrophy.They comprise chronic low back pain, advanced age (advanced age), central nervous system (CNS) damage, peripheral nerve injury, Spinal injury, chemical lesion, central nervous system (CNS) infringement, peripheral lesion, spinal cord lesion, chemical lesion, burn, when four limbs are fixed and are in hospital for a long time because of i or I, take place useless in sexual maladjustment (disuse deconditioning) and alcoholism.
Complete androgen receptor (AR) signal transduction pathway is very crucial for the suitable growth of skeletal muscle.And complete AR signal transduction pathway increases the synthetic of thin muscle mass, muscle strength and mytolin.
If myatrophy does not weaken, can cause fearful health consequences.For example, the variation that takes place in the myatrophy process can cause physical appearance to die down, and this health to individuality is harmful, and the susceptibility that causes fracturing strengthens and the energy level weakness.And myatrophy is to suffer from the strong omen of patient's M ﹠ M of emaciation and AIDS.
All be badly in need of new innovative approach in basic science and clinical level and be used for following compound: a) male contraception with exploitation; B) the relevant illness of the various hormones of treatment, for example with old and feeble male sex's male sex hormone go down (ADAM) relevant illness, for example fatigue, depression, sexual desire reduction, sexual dysfunction, erective dysfunction, hypogonadism, osteoporosis, alopecia, anaemia, obesity, Sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, mood and cognitive change and prostate cancer; C) the treatment illness relevant, for example sexual dysfunction, sexual desire reduction, hypogonadism, Sarcopenia, osteopenia, osteoporosis, cognition and mood change, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer with ADIF; D) treat and/or prevent chronic myatrophy or Sarcopenia; E) reduce prostate cancer sickness rate, end prostate cancer or cause that prostate cancer disappears; F) oral androgenic substitutes and/or other clinical treatment and/or diagnostic field.
A variety of diseases and/or illness all are subjected to the influence of hypogonadism and katabolism effect, comprise ephrosis, central nervous system injury, burn and chronic wounds.
In the U.S., the sickness rate of renal failure rises and is very general.Patient's quantity of registration end-stage renal disease (ESRD) Medical Benefits Fund project reaches 431284 people from 86354 people that about 10,000 beneficiaries in 1973 increase to nineteen eighty-three on December 3rd, 2002.Singly be 2002, just have 100359 patients to participate in U.S. ESRD project.Chronic nephropathy (CKD) is the tendency of ESRD, and it takes place when kidney can not be got rid of refuse fully in body.CKD is a kind of PD lentamente, and wherein, diabetes, hypertension and anaemia may be concurrent illnesss.
CKD uses the system by stages of the available renal function of expression to diagnose (the 1st phase=normal renal function), and the patient symptom can not occur in early days usually.The 5th phase of CKD is ESRD, and it is fully or near renal failure completely, and usually occurs in renal function and be lower than 10% o'clock of baseline.
The simultaneous phenomenon relevant with ESRD comprise hypogonadism, unwillingly lose weight, tired or the like.
Burn causes testosterone minimizing, nitrogen level to descend and bone mineral density (BDM) reduces, these continued 1 year after damage even possibly, and with poor wound healing, infection risk increase, lean mass minimizing, recovery is obstructed and the survivor that delays to burn reintegrates into society relevant.The katabolism effect that causes because of burn causes significantly and unwillingly loses weight, and further complicates the issue.
Spinal injury (SCI) may cause changing the secretion and the generation of central neurotransmitter, and this may cause the hypothalmus-pituitary-adrenal axis dysfunction then, causes the decline of testosterone and other hormonal readiness.SCI or other acute illness or wound comprise on feature that katabolism strengthens and follow the anabolism activity to weaken, cause the illness that is easy to lose weight reducing body tissue.As long as catabolic process does not interrupt, so Wen Luan nutritional utilization will continue.The influence of loss lean mass comprises wound expansion and healing mechanism of damaged.Because it is fixing that malnutritive and hypoproteinosis adds, the patient of Spinal injury is in the risk of trouble bedsore highly.
Chronic wounds can be caused by any kind of illness, comprises diabetes, circulatory problems, fixes or the like.What make disease complicated (for example in diabetes) is neuropathy to occur, and it increases the risk of ulcer of foot.
Though the processing and the treatment of many these illnesss are arranged, all undesirable.Because it is synthetic to have shown that androgen receptor (AR) signal transduction pathway increases thin muscle mass, muscle strength and mytolin, and because hypogonadism is followed these illnesss, so the molecule of target AR signal transduction pathway can be used for the treatment of these diseases and/or illness.
Summary of the invention
In one embodiment, the invention provides the compound of representing by the structure of formula I:
Figure A20078003470100401
Wherein
X is C or N; W is C or N;
X 1Be N, NH, N (C 1-4Alkyl), NAc, NCOOH or key; Perhaps X 1And X 3With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 1And X 5With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist;
P is H or formula II:
Figure A20078003470100402
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key; Perhaps X 2And R 3With X 2The X that is connected 1Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 2And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist;
X 3Be C 1-4Alkylidene group, NH, N, CH (OH), key; Perhaps X 1And X 3With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 3And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 3And X 4Form two keys together or form the first ring of saturated or unsaturated, replacement or unsubstituted 3-6 together;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key; Perhaps X 4And X 5With X 4And X 5The X that is connected 3Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 3And X 4Form two keys together or form the first ring of saturated or unsaturated, replacement or unsubstituted 3-6;
X 5Be carbon or X 5And X 1With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 5And X 2Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 5And X 3Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Or X 5And X 4With X 5And X 4The X that is connected 3Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist;
A does not exist, or H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2Perhaps A and R form the represented two keys of formula III:
Figure A20078003470100411
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CH 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, halogenide, CF 3, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, NH 2, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN, NO 2Or R 3And X 2And and R 3The phenyl ring and and the X that link to each other 2The X that links to each other 1Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring;
R ' is NH 2, OH or CH 3
R 4And R 5Be H, CH independently 3, halogenide, OH, C 1-4Alkyl, C 1-6Cycloalkyl, halo (C 1-4Alkyl), phenyl, aryl, C 4-8Heterocyclylalkyl or hydroxyl (C 1-4Alkyl);
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is that OH and A are alkyl or haloalkyl, X so 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], N[CH 2CH 2N (CH 3) 2], P (O) (C 1-4Alkyl) or N (O) [CH 2CH 2N (CH 3) 2];
Perhaps
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is OH or OAlk and X 4Be O, S, NH, S, SO, SO 2Or alkylidene group, A is CN, CH so 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Perhaps
If P is a phenyl, X is C, X 1Be NH, X 2Be C (O), R is that OH and A are COOH, X 3Be key, X 4Be CH 2, R 1, R 2Be H, Q is not H so.
Perhaps
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is H, X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2, and X 4Be key or CH 2, R1 and R 2Be H, Q is not H or halogen so
Perhaps
If P is formula II, R 3Be H, X and W are C, X 1And X 5With X 1And X 5The X that is connected 2Xing Cheng oxazolidinedione together, R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
In another embodiment, the compound of formula I is represented by following structure:
In another embodiment, the compound of formula I is represented by following structure:
Figure A20078003470100432
In one embodiment, the invention provides the compound of representing by the structure of formula IV:
Figure A20078003470100433
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CH 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, NH 2, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the compound of formula IV is represented by following structure:
Figure A20078003470100441
In another embodiment, the compound of formula IV is represented by following structure:
Figure A20078003470100442
In one embodiment, the invention provides the compound of representing by the structure of formula VI:
Figure A20078003470100443
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CH 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the compound of formula VI is represented by following structure:
Figure A20078003470100451
In one embodiment, the compound of formula VI is represented by following structure:
Figure A20078003470100461
In one embodiment, the invention provides the compound of representing by the structure of formula XXII:
Figure A20078003470100462
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.In another embodiment, the compound of formula XII is represented by following structure:
In another embodiment, the compound of formula XII is represented by following structure:
Figure A20078003470100472
In one embodiment, the invention provides the compound of representing by the structure of formula XIII:
Figure A20078003470100473
A such as above wherein described in the compounds X II.
In one embodiment, the invention provides the compound of representing by the structure of formula XIII:
Figure A20078003470100474
In one embodiment, the invention provides the compound of representing by the structure of formula XVII:
Wherein
X 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2];
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2] CHF 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br; And
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br.
In another embodiment, the compound of formula XVII is represented by following structure:
In another embodiment, the compound of formula XVII is represented by following structure:
Figure A20078003470100482
In one embodiment, the invention provides the compound of representing by the structure of formula XIX:
Figure A20078003470100483
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 3Be C 1-4Alkylidene group, NH, N, CH (OH) or key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2, and X 4Be key or CH 2, R 1And R 2Be H, Q is not H or halogen so.
In another embodiment, the compound of formula XIX is represented by following structure:
Figure A20078003470100491
In another embodiment, the compound of formula XIX is represented by following structure:
Figure A20078003470100501
In one embodiment, the invention provides the compound of representing by the structure of formula XX:
Figure A20078003470100502
Wherein
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the compound of formula I is represented by following structure:
Or in another embodiment,
Figure A20078003470100512
In one embodiment, the invention provides the compound of representing by the structure of formula XXI:
Figure A20078003470100513
Wherein A, Z, Y, X 4, Q, R 1And R 2As described in the compounds X X.
In another embodiment, the compound of formula XXI is represented by following structure:
Or in another embodiment,
Figure A20078003470100515
In one embodiment, the invention provides the compound of representing by the structure of formula XXII:
Figure A20078003470100521
Wherein A, Z, Y, X 4, Q, R 1And R 2As described in the compounds X X, R 7Be H or oxo, R 8Be H or=CH 2
In another embodiment, the compound of formula XXII is represented by following structure:
Figure A20078003470100522
Or in another embodiment,
Figure A20078003470100523
In one embodiment, the invention provides the compound of representing by the structure of formula XXIII:
Figure A20078003470100524
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIII:
Figure A20078003470100531
Wherein Z, Y, X 4, Q, R 1, R 2And R 3As described in the compounds X XIII.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIV:
Figure A20078003470100532
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXVII:
Figure A20078003470100541
Wherein
X, X 2, X 4, Z, Y, Q, R1 and R 3As above described in the compounds X XXIV.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXVIII:
Figure A20078003470100542
Wherein X, X 2, X 4, Z, Y, Q, R1 and R 3As above described in the compounds X XXIV.
In another embodiment, the compound of formula XXXVIII is represented by following structure:
Or in another embodiment,
Figure A20078003470100552
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIX:
Figure A20078003470100553
Wherein:
X is C or N; W is C or N;
G is O, NH, NC 1-4Alkyl, NC 1-4Acyl group, S, CHC 1-4Alkyl, CHC 1-4Acyl group, C (C 1-4Acyl group) 2, C (C 1-4Alkyl) 2Or (CH 2) n, wherein n is 1-3;
T is S or O;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of formula XLII:
Wherein X, X 4, Z, Y, Q, R1, R 2And R 3As above described in the compounds X XXIX.
In one embodiment, the invention provides the compound of formula XLIV:
Figure A20078003470100562
Wherein:
X, X 4, R, R 1, R 2, R 3, Z, Y and Q such as above described in the compounds X XXIX;
Wherein
If X is C, X 4Be O, NH or S, R 1, R 2And R 3Be that H and R are H, Q is not halogen, H or CN so.
In another embodiment, the compound of formula XLIV is represented by following structure:
Figure A20078003470100571
In one embodiment, the invention provides the compound of representing by the structure of formula XLVII:
Figure A20078003470100572
In one embodiment, the invention provides composition, it comprises compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of formula (I).
In one embodiment, described compound is SARM (SARM).In one embodiment, described SARM is a partial agonist.In one embodiment, described SARM is the tissue selectivity agonist, or in some embodiments, is the tissue selectivity antagonist.
In one embodiment, the invention provides a kind of in male method of contraception, described method comprises to the effective step that suppresses formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of the amount that sperm produces in the described individuality or contain their composition of described individual administration, is implemented in the contraception in the described individuality thus.
In one embodiment, the invention provides methods of hormonal treatment, described method comprises formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination that makes individual androgen receptor and the amount that effectively realizes change androgen-dependent illness or contains the step that their composition contacts.
In one embodiment, the invention provides treatment and suffer from the method for individuality of prostate cancer, described method comprise to described individual administration effectively the amount of the prostate cancer in the described individuality of treatment formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination or contain the step of their composition.
In one embodiment, the invention provides the method for progress of the prostate cancer of the individuality that delays to suffer from prostate cancer, described method comprises to described individual administration and effectively delays formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of the amount of the progress of prostate cancer in the described individuality or contain the step of their composition.
In one embodiment, the invention provides the illness that the individual bone photo of treatment closes or increase individual bone amount, promote individual osteoplastic method, formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of the amount effective dosage of the illness of closing with the described bone photo of effective treatment or contain their composition.
According to this on the one hand, in one embodiment, described individuality is suffered from osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility, bone mineral density (BMD) is lost or their arbitrary combination.In one embodiment, described method increases the bone strength of described individuality.In one embodiment, described compound promoted or reinforcement osteoblast differentiation, perhaps in another embodiment, described compound suppresses osteoclast propagation.
In one embodiment, the invention provides the individual muscular atrophy of treatment, reduce its sickness rate, delay its progress, alleviate its seriousness or alleviate method related indication with it, described method comprise to described individual administration effectively the amount of the described muscular atrophy of the described individuality of treatment formula (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination or contain the step of their composition.
According to this on the one hand, in one embodiment, described muscular atrophy is owing to symptom, illness, disease or illness.In one embodiment, described symptom, illness, disease or illness are neuropathic, infective, chronic or genetic.In one embodiment, described symptom, illness, disease or illness are muscular dystrophy, myatrophy, X (X-linked) spinobulbar muscular atrophy (SBMA), emaciation, malnutrition, leprosy, diabetes, nephropathy, chronic obstructive pulmonary disease (COPD), cancer, whole latter stage renal failure, Sarcopenia, pulmonary emphysema, osteomalacia, HIV infection, AIDS or myocardosis.
In one embodiment, described muscular atrophy is a relevant muscular atrophy of age, and is useless in the relevant muscular atrophy of sexual maladjustment; Perhaps described muscular atrophy is owing to chronic low back pain, burn, central nervous system (CNS) damage or infringement, peripheral nerve injury or infringement, Spinal injury, chemical lesion or infringement or alcoholism.
In one embodiment, the invention provides the treatment human individual diabetes, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment human individual glucose intolerance, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment human individual hyperinsulinemia, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment human individual insulin resistant, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment disease relevant with diabetes, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment human individual fatty liver disease, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the treatment human individual cardiovascular disorder, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the individual emaciation of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the individual ophthalmic of treatment or the method for illness, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.In one embodiment, described ophthalmic or illness comprise sjogren syndrome or xeropthalmus.
In one embodiment, the invention provides the method that reduces individual fat quantity, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, the invention provides the method that increases individual lean mass, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides the individual emaciation of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, described emaciation is relevant with the cancer of described individuality.
In another embodiment, the invention provides the individual rheumatoid arthritis of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides the individual chronic nephropathy of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides the individual end stagerenaldisease of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides the individual fragility (frailty) of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides the individual hypogonadism of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides and a kind ofly treat the relevant hypofunction of individual age, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to described individual Medicine-feeding type (I) compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
In another embodiment, the invention provides following method: suppress spermatogeny; Male contraceptive; Hormonotherapy; The treatment prostate cancer; Delay the progress of prostate cancer; Treat disease or bone amount that increases individuality and/or the individual bone forming of promotion that individual bone photo closes; Treat muscular atrophy, reduce its sickness rate, delay its process, alleviate its seriousness or alleviate relative symptom; Treat diabetes, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat glucose intolerance, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat hyperinsulinemia, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat insulin resistant, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat the disease relevant, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity with diabetes; Treat fatty liver disease, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat cardiovascular disorder, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treat emaciation, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce its morbidity; Treatment ophthalmic or illness; Reduce fat quantity; Or increasing individual lean mass, described method comprises formula (I) compound to described individual effective dosage and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination, and is as described herein.
Brief Description Of Drawings
Particularly point out and clearly claimed at the conclusion part of specification sheets as theme of the present invention.But, by when reading accompanying drawing, understanding best about tissue of the present invention and working method and target thereof, feature and advantage, wherein with reference to following specific descriptions:
Fig. 1 has described the structure (Figure 1A) and their synthetic route of various SARM analogues, for example the compound (Fig. 1 D) of compounds X III (Figure 1B), compound V (Fig. 1 C), formula XI, compounds X XXV (Fig. 1 E), compounds X XXVI (Fig. 1 F), compounds X LVI (Fig. 1 G), compounds X (Fig. 1 H), compounds X XIV-XXVIII (Fig. 1 I), compounds X L (Fig. 1 J), compounds X LI (Fig. 1 K).
Fig. 2 has described the synthetic route of preparation formula XLIII (oxatidyldione) compound.
Fig. 3 has described the synthetic route of preparation formula XLVIII compound.
Fig. 4 has described the synthetic route of preparation formula XLIX compound.
Fig. 5 has described the synthetic route of preparation formula LII compound.
Fig. 6 has described the synthetic route of preparation formula L compound.
Fig. 7 has described the synthetic route of preparation formula LI compound.
Fig. 8 has described the transcriptional activation of bicalutamide analogue by the wild-type androgen receptor.Before part shown in the usefulness is handled, with hAR and the of short duration transfection CV-1 of androgen-dependent luciferase reporter gene construct cell.Report the increase multiple (n=6) of the contrast of relative vehicle treated.
Fig. 9 has described S-4 shown in the table 1 (Fig. 9 A) and androgenic activity and the anabolic activity of testosterone (Fig. 9 B) in the rat of castration.The male rat of castration acceptable dose increases in 14 days testosterone (last figure) or S-4 (figure below).When putting to death, measure the organ weight, be expressed as the percentage ratio of complete contrast.
Figure 10 has described S-4 as shown in table 1, S-1, X-2, X-3, X-5 and X-4, and (X is respectively O, O, S, SO 2, CH 2And NH) ball-rod model that atom is hidden with the synergetic bond with carbon hydrogen of color differentiating.Agonist S-4With X-2And S-1The six-membered cyclic NH-X hydrogen bond configuration of the arylprop acid amides not being supposed before demonstrating.
Figure 11 describes DHT, Sch 16423 (HF), bicalutamide (bical) and the S-4 transcriptional activation by wild-type or mutant androgen receptor.The of short duration transfection CV-1 of expression vector cell with wild-type or mutant AR and androgen-dependent reporter gene construct.Report inducing of each medicine (100nM) AR-mediation, be expressed as relative luciferase unit divided by betagalactosidase activity (stdn contrast).
Figure 12 has described the crystalline structure of androgen receptor ligand binding domain (AR LBD).The front view of the overall structure of Figure 12 A demonstration and R-bicalutamide bonded mutant AR LBD (W741L).Figure 12 B shows that the Fo-Fc simulated annealing omitted the R-bicalutamide economizes the W741L-R-bicalutamide in the sketch map and the electron density map of R-bicalutamide.
Figure 13 describes the stereoscopic overlap of wild-type DHT, T877A-HF and W741L-R-bicalutamide, show steroid in conjunction with planar general survey (Figure 13 A) and steroid in conjunction with planar side-view (Figure 13 B).
Figure 14 has described and R-bicalutamide bonded mutant W741L androgen receptor ligand binding domain.The side-view of the overall structure of Figure 14 A demonstration and R-bicalutamide bonded AR LBD (W741L).AF2 district ( spiral 3,4 and 12) highlights with green.Conservative electric charge-hair clip (charge-clamp) residue is K720 among the H3 and the E897 among the H12.The CONSTRUCTED SPECIFICATION in the AF2 district of Figure 14 B demonstration and DHT bonded wild-type AR LBD.The W741 side chain is presented at and is full of in the atoms in space.
Should be understood that simply clearly for what illustrate, the element shown in the described figure is not necessarily drawn in proportion.For example, for clear, some size of component may be amplified with respect to other element.And in the place that sees fit, the possibility repeat reference numerals is to indicate corresponding or similar elements in described figure.
Detailed Description Of The Invention
In following specifying, narrated a large amount of details and thoroughly understood this to provide Bright. Yet, person of skill in the art will appreciate that do not have these details also can implement the present invention. In some other situation, well-known method, process and component are not described in detail so that unlikely Make the present invention's ambiguous that becomes.
In one embodiment, the invention provides compound by the representation of formula I:
Figure A20078003470100631
Wherein
X is C or N; W is C or N;
X 1N, NH, N (C1-4Alkyl), NAc, NCOOH or key; Perhaps X1And X3With X1And X3The X that connects2And X5Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring; Perhaps X1And X5With X1And X5The X that connects2Form together saturated or insatiable hunger With, replace or unsubstituted 5-or 6-unit ring, and A does not exist;
P is H or formula II:
Figure A20078003470100641
X 2C1-4Alkylidene, SO2、C(O)、CH-[CH 2-(C 4-8Ring)], CH (C1-4Alkyl), CH (NH2)、CH(OH)、CH(C 1-4Haloalkyl), key; Perhaps X2And R3With X2The X that connects1Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring; Perhaps X2And X5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not deposit ;
X 3C1-4Alkylidene, NH, N, CH (OH), key; Perhaps X1And X3With X1And X3The X that connects2And X5Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-Unit's ring; Perhaps X3And X5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit Ring, and A does not exist; Perhaps X3And X4Form together two keys or form together saturated or unsaturated , replace or unsubstituted 3-6 unit ring;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key; Perhaps X4And X5And and X4And X5The X that connects3Form together saturated or unsaturated, that replace or unsubstituted 5-Or 6-unit ring, and A does not exist; Perhaps X3And X4Form together two keys or form together saturated or The first ring of undersaturated, replacement or unsubstituted 3-6;
X 5Carbon or X5And X1With X1And X5The X that connects2Form together saturated or unsaturated , replace or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X5And X2Form saturated Or undersaturated, replace or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X5And X3Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X5And X4With X5And X4The X that connects3Form together saturated or unsaturated, replacement Or unsubstituted 5-or 6-unit ring, and A does not exist;
A does not exist, or H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、 CN、CH 2OH、CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、 CHO、C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2 Perhaps A and R Form the represented two keys of formula III:
Figure A20078003470100651
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO2, halide, CF3、C 2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R is H, OH, C1-4Alkyl, CF3、CH 2OH、O(C 1-4Alkyl) or O (C1-4Acyl group);
R 1H, OH, NH2, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN, NO2 Perhaps R3And X2With R3The phenyl ring that connects and X2The X that connects1Form together saturated or unsaturated, that replace or unsubstituted 5-Or 6-unit ring;
R ' is NH2, OH or CH3；
R 4And R5H, CH independently3, halide, OH, C1-4Alkyl, C1-6Cycloalkyl, halo (C1-4Alkyl), phenyl, aryl, C4-8Heterocyclylalkyl or hydroxyl (C1-4Alkyl);
R 6CN, NO2、NHC(O)CH 3Or halide;
Wherein
If P is formula II, X is C, X1NH, X2C (O), X3CH2, R is that OH and A are alkyl or haloalkyl, so X4S (O) [=CHCH2N(CH 3) 2]、 C(OH)[CH 2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、N[CH 2CH 2N(CH 3) 2]、P(O)(C 1-4Alkyl) or N (O) [CH2CH 2N(CH 3) 2]；
Perhaps
If P is formula II, X is C, X1NH, X2C (O), X3CH2, R is OH or OAlk and X4O, S, NH, S, SO, SO2Or thiazolinyl, A is CN, CH so2OH、 CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、CHO、 C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Perhaps
If P is phenyl, X is C, X1NH, X2Be C (O), R is that OH and A are COOH, X3Key, X4CH2，R 1、R 2Be H, Q is not H so;
Perhaps
If P is formula II, X is C, X3CH2，X 4O or NH, R1、R 2And R3H, and X5And X1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is H, X is C, X1NH, X2Be C (O), R is OH, and A is alkyl, X3Key or CH2, and X4Key or CH2，R 1And R2Be H, Q is not H or halogen so;
Perhaps
If P is formula II, R3Be H, X and W are C, X1And X5With X1And X5The X that connects2Xing Cheng oxazolidinedione, R is alkyl, X3CH2, and X4O, NH, S, SO2Or CH2, Q is not halide so.
In another embodiment, the compound of formula I is by following representation:
Figure A20078003470100661
In another embodiment, the compound of formula I is by following representation:
In one embodiment, the invention provides compound by the representation of formula IV:
Figure A20078003470100671
Wherein
X is C or N; W is C or N;
X 2C1-4Alkylidene, SO2、CH-[CH 2-(C 4-8Ring)], CH (C1-4Alkyl), CH (NH2)、 CH(OH)、CH(C 1-4Haloalkyl), key;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
A is H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、CN、CH 2OH、 CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、CHO、 C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、 CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、CN、NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R is H, OH, C1-4Alkyl, CF3、CH 2OH、O(C 1-4Alkyl) or O (C1-4Acyl group);
R 1H, OH, NH2, F, Cl, Br or I;
R 2H, R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-to cyano-phenyl or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
In another embodiment, the compound of formula IV is by following representation:
Figure A20078003470100681
In another embodiment, the compound of formula IV is by following representation:
Figure A20078003470100682
In one embodiment, the invention provides compound by the representation of formula VI:
Figure A20078003470100683
Wherein
X is C or N; W is C or N;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
A is H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、CN、CH 2OH、 CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、CHO、 C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、 CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、CN、NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R is H, OH, C1-4Alkyl, CF3、CH 2OH、O(C 1-4Alkyl) or O (C1-4Acyl group);
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
In another embodiment, the compound of formula VI is by following representation:
Figure A20078003470100691
In one embodiment, the compound of formula VI is by following representation:
Figure A20078003470100692
In one embodiment, the invention provides compound by the representation of formula XII:
Figure A20078003470100693
Wherein
X is C or N; W is C or N;
X 4O, S, SO, S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、NO、 C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
A is CN, CH2OH、CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、 CH 2NCS、CHO、C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、CN、NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R 1H, OH, F, Cl, Br or I;
R 2H, by R5The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
In another embodiment, the compound of formula XII is by following representation:
Figure A20078003470100701
In another embodiment, the compound of formula XII is by following representation:
In one embodiment, the invention provides compound by the representation of formula XIII:
Figure A20078003470100711
A such as above described in the compounds X II wherein.
In one embodiment, the invention provides compound by the representation of formula XIII:
Figure A20078003470100712
In one embodiment, the invention provides compound by the representation of formula XVII:
Figure A20078003470100713
Wherein
X 4S (O) [=CHCH2N(CH 3) 2]、C(OH)[CH 2CH 2N(CH 3) 2]、 C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、 NO[CH 2CH 2N(CH 3) 2]；
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br; And
Y is H, C1-4Alkyl, CF3、CN、NO 2, F, Cl, I or Br.
In another embodiment, the compound of formula XVII is by following representation:
In another embodiment, the compound of formula XVII such as following representation:
Figure A20078003470100722
In one embodiment, the invention provides compound by the representation of formula XIX:
Figure A20078003470100723
Wherein
X is C or N; W is C or N;
X 2C1-4Alkylidene, SO2、C(O)、CH-[CH 2-(C 4-8Ring)], CH (C1-4Alkyl), CH (NH2)、CH(OH)、CH(C 1-4Haloalkyl), key;
X 3C1-4Alkylidene, NH, N, CH (OH) or key;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
A is H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、CN、CH 2OH、 CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、CHO、 C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、 CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide;
Wherein
If X is C, X1NH, X2Be C (O), R is OH, and A is alkyl, X3Key or CH2, and X4Key or CH2, R1 and R2Be H, Q is not H or halogen so.
In another embodiment, the compound of formula XIX is by following representation:
Figure A20078003470100731
In another embodiment, the compound of formula XIX is by following representation:
Figure A20078003470100732
In one embodiment, the invention provides compound by the representation of formula XX:
Figure A20078003470100741
Wherein
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
A is H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、CN、CH 2OH、 CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、CHO、 C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、 CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2；
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
In another embodiment, the compound of formula I is by following representation:
Or in another embodiment,
Figure A20078003470100751
In one embodiment, the invention provides compound by the representation of formula XXI:
Figure A20078003470100752
Wherein A, Z, Y, X4、Q、R 1And R2As described in the compounds X X.
In another embodiment, the compound of formula XXI is by following representation:
Figure A20078003470100753
Or in another embodiment,
In one embodiment, the invention provides compound by the representation of formula XXII:
Figure A20078003470100755
Wherein A, Z, Y, X4, Q, R1And R2As described in the compounds X X, R7Be H or
Oxo, R8Be H or=CH2。
In another embodiment, the compound of formula XXII is by following representation:
Figure A20078003470100761
Or in another embodiment,
In one embodiment, the invention provides compound by the representation of formula XXIII:
Figure A20078003470100763
Wherein
X is C or N; W is C or N;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF3、NO 2, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
In one embodiment, the invention provides compound by the representation of formula XXXIII:
Wherein Z, Y, X4, Q, R1 and R3As described in the compounds X XIII.
In one embodiment, the invention provides compound by the representation of formula XXXIV:
Figure A20078003470100772
Wherein
X is C or N; W is C or N;
X 2C1-4Alkylidene, SO2、C(O)、CH-[CH 2-(C 4-8Ring)], CH (C1-4Alkyl), CH (NH2)、CH(OH)、CH(C 1-4Haloalkyl), key;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO2、CF 3, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R 6CN, NO2、NHC(O)CH 3Or halide.
In one embodiment, the invention provides compound by the representation of formula XXXVII:
Figure A20078003470100781
Wherein
X、X 2、X 4、Z、Y、Q、R 1And R3As above described in the compounds X XXIV.
In one embodiment, the invention provides compound by the representation of formula XXXVIII:
Figure A20078003470100782
Wherein X, X2、X 4, Z, Y, Q, R1 and R3As above described in the compounds X XXIV.
In another embodiment, the compound of formula XXXVIII is by following representation:
Or in another embodiment,
Figure A20078003470100791
In another embodiment, the X of compounds X XXVIII4O. In another enforcement side In the case, the X of compounds X XXVIII2C (O). In another embodiment, compounds X XXVIII X2CH2 In another embodiment, the Q of compounds X XXVIII is CN. At another In the individual embodiment, the Z of compounds X XXVIII is CN, and Y is CF3。
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X1And X5With X1And X5The X that connects2Form together saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring;
Wherein
If P is formula II, X is C, X3CH2，X 4O or NH, R1、R 2And R3H, and X5And X1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is formula II, R3Be H, X and W are C, X1And X5With X1And X5The X that connects2Xing Cheng oxazolidinedione together, R is alkyl, X3CH2, and X4O, NH, S, SO2Or CH2, Q is not halide so.
In another embodiment, described saturated or unsaturated, that replace or unsubstituted 5-Or 6-unit ring is pyrrolidines, piperidines, morpholine, succinimide, oxazolidine, oxazolidinedione Huo Evil Oxazolidone.
In one embodiment, the invention provides compound by the representation of formula XXXIX:
Figure A20078003470100792
Wherein:
X is C or N; W is C or N;
G is O, NH, NC1-4Alkyl, NC1-4Acyl group, S, CHC1-4Alkyl, CHC1-4Acyl group, C (C1-4Acyl group)2、C(C 1-4Alkyl)2Or (CH2) n, wherein n is 1-3;
T is S or O;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key;
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF3、NO 2, halide, C2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R is H, OH, C1-4Alkyl, CF3、CH 2OH、O(C 1-4Alkyl) or O (C1-4Acyl group);
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3H, C1-4Alkyl, halide, CN or NO2；
R ' is NH2, OH or CH3 And
R 6CN, NO2、NHC(O)CH 3Or halide.
Wherein
If R3Be H, X and W are C, and G is O, and T is O, and R is alkyl, X3CH2, and X4O, NH, S, SO2Or CH2, Q is not halide so.
In one embodiment, the invention provides the compound of formula XLII:
Figure A20078003470100801
Wherein X, X4、Z、Y、Q、R1、R 2And R3As above described in the compounds X XXIX.
In one embodiment, the invention provides the compound of formula XLIV:
Wherein:
X、X 4、R、R 1、R 2、R 3, Z, Y and Q such as above described in the compounds X XXIX;
Wherein
If X is C, X4O, NH or S, R1、R 2And R3That H and R are H, so Q is not halogen, H or CN.
In another embodiment, the compound of formula XLIV is by following representation:
Figure A20078003470100812
In one embodiment, the invention provides compound by the representation of formula XLVII:
Figure A20078003470100813
In one embodiment, the invention provides compound by the representation of formula I:
Figure A20078003470100814
Wherein
X is C or N; W is C or N;
X 1N, NH, N (C1-4Alkyl), NAc, NCOOH or key; Perhaps X1And X3With X1And X3The X that connects2And X5Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring; Perhaps X1And X5With X1And X5The X that connects2Form together saturated or insatiable hunger With, replace or unsubstituted 5-or 6-unit ring, and A does not exist;
P is H or formula II:
X 2C1-4Alkylidene, SO2、C(O)、CH-[CH 2-(C 4-8Ring)], CH (C1-4Alkyl), CH (NH2)、CH(OH)、CH(C 1-4Haloalkyl), key; Perhaps X2And R3With X2The X that connects1Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring; Perhaps X2And X5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not deposit ;
X 3C1-4Alkylidene, NH, N, CH (OH), key; Perhaps X1And X3With X1And X3The X that connects2And X5Form together saturated or unsaturated, replacement or unsubstituted 5-or 6-Unit's ring; Perhaps X3And X5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit Ring, and A does not exist; Perhaps X3And X4Form together two keys or form together saturated or unsaturated , replace or unsubstituted 3-6 unit ring;
X 4O, S, SO, C (O), S (O) [=CHCH2N(CH 3) 2]、SO 2、NH、NHR’、 NO、C 1-4Alkylidene, C (OH) [CH2CH 2N(CH 3) 2]、C[＝CHCH 2N(CH 3) 2]、PO(C 1-4Alkyl), N[CH2CH 2N(CH 3) 2]、NO[CH 2CH 2N(CH 3) 2] or key; Perhaps X4And X5With X4And X5The X that connects3Form together saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X3And X4Form together two keys or form saturated or unsaturated , replace or unsubstituted 3 to 6 yuan of rings;
X 5Carbon or X5And X1With X1And X5The X that connects2Form together saturated or unsaturated, That replace or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X5And X2Form saturated or Undersaturated, replace or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X5And X3Shape Become saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Or X5And X4With X5And X4The X that connects3Form together saturated or unsaturated, replace or not The 5-that replaces or 6-unit ring, and A does not exist;
A does not exist, or H, OH, SH, NH2、C 1-4Alkyl, CHF2、CH 2F、CF 3、 CN、CH 2OH、CH 2O(C 1-4Alkyl), CH2O(C 1-4Acyl group), CH2CN、CH 2N 3、CH 2NCS、 CHO、C(O)O(C 1-4Alkyl), CONHR ', C (O) N (R ')2、C(O)O(C 1-4Alkyl), C (O) R ', CH2CF 3、CF 2CF 3、CH 2OR’CH 2C(O)CH＝CH 2Or C (O) CH=CH2 Perhaps A and R Form the represented two keys of formula III:
Figure A20078003470100831
Z is H, CN, NO2、NHC(O)CH 3、C 1-4Alkyl, F, Cl, I or Br;
Y is H, C1-4Alkyl, CF3、NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO2, halide, CF3、C 2-6Thiazolinyl, C2-6Alkynyl, C (O) CH2NH 2、 C(O)NH(C 1-4Alkyl), C (O) N (C1-4Alkyl)2、C(O)NH 2、NH(C 1-4Alkyl), NHC (O) NH (C1-4Alkyl), CH2C(O)NH 2、NHC(O)NH 2、NHCO(C 1-4Alkyl), NHSO2(C 1-4Alkyl), O-[CH2CH 2CH(CH 3) 2]、O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)]2CH 2N(CH 3) 2]；
R is H, OH, C1-4Alkyl, CF3、CH 2OH、O(C 1-4Alkyl) or O (C1-4Acyl group);
R 1H, OH, F, Cl, Br or I;
R 2H, by R6The benzyl, (CH that replace2) 2-O-is to cyano-phenyl, CH2-O-is to cyano-phenyl Or CH=CH-O-is to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN, NO 2Or R 3And X 2And and R 3The phenyl ring and and the X that link to each other 2The X that links to each other 1Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring;
R ' is NH 2, OH or CH 3
R 4And R 5Be H, CH independently 3, halogenide, OH, C 1-4Alkyl, C 1-6Cycloalkyl, halo (C 1-4Alkyl), phenyl, aryl, C 4-8Heterocyclylalkyl or hydroxyl (C 1-4Alkyl);
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is that OH and A are alkyl or haloalkyl, X so 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], N[CH 2CH 2N (CH 3) 2], P (O) (C 1-4Alkyl) or N (O) [CH 2CH 2N (CH 3) 2];
Perhaps
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is OH or OAlk and X 4Be O, S, NH, S, SO, SO 2Or alkylidene group, A is CN, CH so 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Perhaps
If P is a phenyl, X is C, X 1Be NH, X 2Be C (O), R is that OH and A are COOH, X 3Be key, X 4Be CH 2, R 1, R 2Be H, Q is not H so.
Perhaps
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is H, X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2, and X 4Be key or CH 2, R1 and R 2Be H, Q is not H or halogen so;
Perhaps
If P is formula II, R 3Be H, X and W are C, X 1And X 5With X 1And X 5The X that is connected 2Xing Cheng oxazolidinedione together, R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
In one embodiment, the invention provides the compound of representing by the structure of formula IV:
Figure A20078003470100841
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula V:
Figure A20078003470100851
In one embodiment, the invention provides the compound of representing by the structure of formula VI:
Figure A20078003470100861
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula VII:
Figure A20078003470100871
Wherein Z, Y, R 1, R 2, R 3, Q and X 4As above described in the compound VI.
In another embodiment, the invention provides the compound of representing by the structure of formula VIII:
R wherein 1, R 2, Q and X 4As above described in the compound VI.
In one embodiment, the invention provides the compound of representing by the structure of formula IX:
In one embodiment, the invention provides the compound of representing by the structure of formula X:
Figure A20078003470100874
In one embodiment, the invention provides the compound of representing by the structure of formula XI:
Figure A20078003470100875
A such as above wherein described in the compound VI.
In another embodiment, the A of compounds X I is CH 2OH.In another embodiment, the A of compounds X I is CH 2OMe.In another embodiment, the A of compounds X I is CF 3In another embodiment, the A of compounds X I is CH 3In another embodiment, the A of compounds X I is CN.
In one embodiment, the invention provides the compound of representing by the structure of formula XII:
Figure A20078003470100881
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the X of compounds X II 4Be O.In another embodiment, the Q of compounds X II is CN, and R 1And R 2Be H.In another embodiment, the Q of compounds X II is CN, and Z is CN, and Y is CF 3, and R 1, R 2And R 3Be H.In another embodiment, the A of compounds X II is CH 2OH.In another embodiment, the A of compounds X II is CN.
In one embodiment, the invention provides the compound of representing by the structure of formula XIII:
A such as above wherein described in the compounds X II.
In one embodiment, the invention provides the compound of representing by the structure of formula XIV:
Or in another embodiment,
Figure A20078003470100893
In one embodiment, the invention provides the compound of representing by the structure of formula XV:
Figure A20078003470100894
In one embodiment, the invention provides the compound of representing by the structure of formula XVI:
Figure A20078003470100895
In one embodiment, the invention provides the compound of representing by the structure of formula XVII:
Figure A20078003470100901
Wherein
X 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2];
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br; And
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br.
In another embodiment, the Q of compounds X VII is F.In another embodiment, the Q of compounds X VII is CN.In another embodiment, the Z of compounds X VII is CN, and Y is CF 3In another embodiment, the Q of compounds X VII is CN, and Z is CN, and Y is CF 3
In one embodiment, the invention provides the compound of representing by the structure of formula XVIII:
Figure A20078003470100902
In one embodiment, the invention provides the compound of representing by the structure of formula XIX:
In one embodiment, the invention provides the compound of formula I, wherein X 3And X 4Form two keys together or form the first ring of saturated or unsaturated, replacement or unsubstituted 3-6 together.In another embodiment, the first ring of described 3-6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutene base, cyclopentenyl, cyclohexenyl, benzene, piperidines, pyrroles, tetrahydrofuran (THF), tetramethyleneimine, succinimide, oxazolidine, oxazolidinedione Huo oxazolidone.
In another embodiment, the invention provides the compound of representing by the structure of formula LIII:
The trans LIII-cis of LIII-
In another embodiment, the invention provides the compound of representing by the structure of formula LIV:
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 3Be C 1-4Alkylidene group, NH, N, CH (OH) or key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2, and X 4Be key or CH 2, R 1And R 2Be H, Q is not H or halogen so.
In another embodiment, the X of compounds X IX 2Be CH 2In another embodiment, the X of compounds X IX 2Be C (O).In another embodiment, the X of compounds X IX 3Be CH2.In another embodiment, the X of compounds X IX 4Be O.
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X 2And X 3With X 1Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring.In another embodiment, described saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetramethyleneimine, pyrroles, morpholine, piperidin-4-one-or piperidines.
In one embodiment, the invention provides the compound of representing by the structure of formula XX:
Wherein
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the A of compounds X X is CH 3In another embodiment, the Xx of compounds X X 4Be O.In another embodiment, the Q of compounds X X is CN.In another embodiment, the Z of compounds X X is CN, and Y is CF 3In another embodiment, the Q of compounds X X is CN, and Z is CN, and Y is CF 3In another embodiment, the A of compounds X X is CH 3, X 4Be O, Q is CN, and Z is CN, R 1And R 2Be H, and Y is CF 3
In one embodiment, the invention provides the compound of representing by the structure of formula XXI:
Figure A20078003470100941
Wherein A, Z, Y, X 4, Q, R 1And R 2As described in the compounds X XI.
In another embodiment, the A of compounds X XI is CH 3In another embodiment, the X of compounds X XI 4Be O.In another embodiment, the Q of compounds X XI is CN.In another embodiment, the Z of compounds X XI is CN, and Y is CF 3In another embodiment, the Q of compounds X XI is CN, and Z is CN, and Y is CF 3In another embodiment, the A of compounds X XI is CH 3, X 4Be O, Q is CN, and Z is CN, R 1And R 2Be H, and Y is CF 3
In one embodiment, the invention provides the compound of representing by the structure of formula XXII:
Figure A20078003470100942
Wherein A, Z, Y, X 4, Q, R 1And R 2As described in the compounds X X, R 7Be H or oxo, R 8Be H or=CH 2
In another embodiment, the A of compounds X XII is CH 3In another embodiment, the X of compounds X XII 4Be O.In another embodiment, the R of compounds X XI 7And R 8Be H.In another embodiment, the R of compounds X XII 7Be=CH 2, and R 8It is oxo.In another embodiment, the Q of compounds X XII is CN.In another embodiment, the Z of compounds X XII is CN, and Y is CF 3In another embodiment, the A of compounds X XII is CH 3, X 4Be O, Z is CN, and Q is CN, R 1And R 2Be H, and Y is CF 3
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X 3And X 1With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring.In another embodiment, described saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be piperazine, piperazine-2,6-diketone, piperidines, tetramethyleneimine, pimelinketone, hexanaphthene, tetrahydrobenzene, cyclopentanone, pentamethylene, cyclopentenes, succinimide, oxazolidine, oxazolidinedione Huo oxazolidone.
In one embodiment, the invention provides the compound of representing by the structure of formula XXIII:
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the X of compounds X XIII 4Be O.In another embodiment, the Q of compounds X XIII is CN.In another embodiment, the Z of compounds X XIII is CN, and Y is CF 3In another embodiment, the X of compounds X XIII 4Be O, Z is CN, and Q is CN, R 1, R 2And R 3Be H, and Y is CF 3
In another embodiment, the invention provides the compound of representing by the structure of formula XXIV:
Figure A20078003470100961
In another embodiment, the invention provides the compound of representing by the structure of formula XXV:
Figure A20078003470100962
In another embodiment, the invention provides the compound of representing by the structure of formula XXVI:
Figure A20078003470100963
In another embodiment, the invention provides the compound of representing by the structure of formula XXVII:
Figure A20078003470100964
In another embodiment, the invention provides the compound of representing by the structure of formula XXVIII:
In another embodiment, the invention provides the compound of representing by the structure of formula XXIX:
In another embodiment, the invention provides the compound of representing by the structure of formula XXX:
Figure A20078003470100972
In another embodiment, the invention provides the compound of representing by the structure of formula XXXI:
Figure A20078003470100973
In another embodiment, the invention provides the compound of representing by the structure of formula XXXII:
Figure A20078003470100974
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIII:
Figure A20078003470100981
Wherein Z, Y, X 4, Q, R 1, R 2And R 3As described in the compounds X XIII.
In another embodiment, the X of compounds X XXIII 4Be O.In another embodiment, the Q of compounds X XXIII is CN.In another embodiment, the Z of compounds X XXIII is CN, and Y is CF 3In another embodiment, the X of compounds X XXIII 4Be O, Z is CN, and Q is CN, R 1, R 2And R 3Be H, and Y is CF 3
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X 3And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring.In another embodiment, described saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetrahydrofuran (THF), tetramethyleneimine, piperidines, pimelinketone, hexanaphthene, tetrahydrobenzene, cyclonene, cyclopentanone, cyclopentenone, pentamethylene, cyclopentenes, succinimide, oxazolidine, oxazolidinedione Huo oxazolidone.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIV:
Figure A20078003470100982
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3With
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In another embodiment, the X of compounds X XXIV 4Be O.In another embodiment, the Q of compounds X XXIV is CN.In another embodiment, the X of compounds X XXIV 2Be CH 2In another embodiment, the X of compounds X XXIV 2Be C (O).In another embodiment, the Z of compounds X XXIV is CN, and Y is CF 3In another embodiment, the X of compounds X XXIV 4Be O, Z is CN, and Q is CN, R 1, R 2And R 3Be H, and Y is CF 3
In another embodiment, the invention provides the compound of formula XXXV:
Figure A20078003470100991
In another embodiment, the invention provides the compound of formula XXXVI:
Figure A20078003470100992
In one embodiment, the invention provides the compound of representing by the structure of formula XXXVII:
Figure A20078003470101001
Wherein
X, X 2, X 4, Z, Y, Q, R 1, R 2And R 3As above described in the compounds X XXIV.
In another embodiment, the X of compounds X XXVII 4Be O.In another embodiment, the X of compounds X XXVII 2Be C (O).In another embodiment, the X of compounds X XXVII 2Be CH 2In another embodiment, the Q of compounds X XXVII is CN.In another embodiment, the Z of compounds X XXVII is CN, and Y is CF 3
In one embodiment, the invention provides the compound of representing by the structure of formula XXXVIII:
Figure A20078003470101002
Wherein X, X 2, X 4, Z, Y, Q, R 1, R 2And R 3As above described in the compounds X XXIV.
In another embodiment, the X of compounds X XXVIII 4Be O.In another embodiment, the X of compounds X XXVIII 2Be C (O).In another embodiment, the X of compounds X XXVIII 2Be CH 2In another embodiment, the Q of compounds X XXVIII is CN.In another embodiment, the Z of compounds X XXVIII is CN, and Y is CF 3
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X 1And X 5With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring;
Wherein
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so.
In one embodiment, the invention provides the compound of formula I, wherein P is formula II, X 1And X 5With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring;
Wherein
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is formula II, R 3Be H, X and W are C, X 1And X 5With X 1And X 5The X that is connected 2Xing Cheng oxazolidinedione together, R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
In another embodiment, described saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetramethyleneimine, piperidines, morpholine, succinimide, oxazolidine, oxazolidinedione Huo oxazolidone.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIX:
Figure A20078003470101011
Wherein:
X is C or N; W is C or N;
G is O, NH, NC 1-4Alkyl, NC 1-4Acyl group, S, CHC 1-4Alkyl, CHC 1-4Acyl group, C (C 1-4Acyl group) 2, C (C 1-4Alkyl) 2Or (CH 2) n, wherein n is 1-3;
T is S or O;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula XXXIX:
Figure A20078003470101021
Wherein:
X is C or N; W is C or N;
G is O, NH, NC 1-4Alkyl, NC 1-4Acyl group, S, CHC 1-4Alkyl, CHC 1-4Acyl group, C (C 1-4Acyl group) 2, C (C 1-4Alkyl) 2Or (CH 2) n, wherein n is 1-3;
T is S or O;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide; Wherein
If R 3Be H, X and W are C, and G is O, and T is O, and R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
In one embodiment, the invention provides the compound of formula XL:
Figure A20078003470101031
In one embodiment, the invention provides the compound of formula XLI:
Figure A20078003470101032
In one embodiment, the invention provides the compound of formula XLII:
Wherein X, X 4, Z, Y, Q, R 1, R 2And R 3As above described in the compounds X XXIX.
In one embodiment, the invention provides the compound of formula XLIII:
Figure A20078003470101042
In one embodiment, the invention provides the compound of formula XLIV:
Figure A20078003470101043
Wherein:
X, X 4, R, R 1, R 2, R 3, Z, Y and Q such as above described in the compounds X XXIXV;
Wherein
If X is C, X 4Be O, NH or S, R 1, R 2And R 3Be that H and R are H, Q is not halogen, H or CN so.
In one embodiment, the invention provides the compound of representing by the structure of formula XLV:
Figure A20078003470101044
X wherein 4As above described in the compounds X XXIX.
In one embodiment, the invention provides the compound of representing by the structure of formula XLVI:
Figure A20078003470101051
In one embodiment, the invention provides the compound of representing by the structure of formula XLVII:
Figure A20078003470101052
Wherein
X is N or CH;
Z is H, CN, NO 2, NHC (O) CH 3, CH 3, F, Cl, I or Br;
Y is H, CH 3, CF 3, CN, F, Cl, I or Br;
Q is H, O-(CH 2) 2CH (CH 3) 2Or O-(CH 2) 2N (CH 3) 2
R 1Be H, OH, F, Cl, Br or I;
R 2Be by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, CH 3, halogenide, CN or NO 2
R 4And R 5Be H, CH independently 3, halogenide, OH, C 1-4Alkyl, C 1-6Cycloalkyl, halo (C 1-4Alkyl), phenyl, aryl, heterocycle or hydroxyl-C 1-4Alkyl; And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
In one embodiment, the invention provides the compound of representing by the structure of formula XLVIII:
Figure A20078003470101061
In one embodiment, the invention provides the compound of representing by the structure of formula XLIX:
Figure A20078003470101062
In one embodiment, the invention provides the compound of representing by the structure of formula L:
Figure A20078003470101063
In one embodiment, the invention provides the compound of representing by the structure of formula LI:
Figure A20078003470101071
In one embodiment, the invention provides the compound of representing by the structure of formula LII:
Figure A20078003470101072
In another embodiment, the invention provides the pharmacy acceptable salt of formula (I) compound.In another embodiment, the invention provides the medicine of formula (I) compound.In another embodiment, the invention provides the hydrate of formula (I) compound.In another embodiment, the invention provides the N-oxide compound of formula (I) compound.In another embodiment, the invention provides the polymorph of formula (I) compound.In another embodiment, the invention provides the crystal of formula (I) compound.In another embodiment, the invention provides meta-bolites arbitrarily, isomer, pharmacy acceptable salt, medicine, polymorph, crystal, impurity (impurity), the hydrate of formula (I) compound, the combination of N-oxide compound.
In some embodiments, term " isomer " includes but not limited to optical isomer and analogue, constitutional isomer and analogue, conformer and analogue etc.In one embodiment, term " isomer " is meant the optical isomer that comprises described compound.Person of skill in the art will appreciate that compound of the present invention contains at least one chiral centre.Therefore, employed in the method for the invention compound can exist or separated with optical activity form or racemic form.Some compounds also can show as polymorphism.Should be appreciated that the present invention includes racemic form, optical activity form, polymorphic forms or stereoisomeric forms in any ratio or their mixture arbitrarily, these forms have the character that is used for the treatment of male sex hormone associated conditions as herein described.In one embodiment, described compound is pure (R)-isomer.In another embodiment, described compound is pure (S)-isomer.In another embodiment, described SARM is described (R)-isomer and (S)-mixture of isomers.In another embodiment, described SARM comprises described (the R)-isomer of equivalent and (S)-isomer racemic mixture.How to prepare the optical activity form and be well known in the art (for example, by recrystallization technology split described racemic form, by synthetic by the optical activity raw material, by chirality synthetic or by using chiral stationary phase to carry out chromatographic separation).
In another embodiment, compound of the present invention is described (R)-isomer and described (S)-mixture of isomers.In another embodiment, described mixture comprises described (R)-isomer of 60% and described (S)-isomer of 40%.In another embodiment, described mixture comprises described (R)-isomer of 40% and described (S)-isomer of 60%.In another embodiment, described mixture comprises described (R)-isomer of 70% and described (S)-isomer of 30%.In another embodiment, described mixture comprises described (R)-isomer of 30% and described (S)-isomer of 70%.In another embodiment, described mixture comprises described (R)-isomer of 80% and described (S)-isomer of 20%.In another embodiment, described mixture comprises described (R)-isomer of 20% and described (S)-isomer of 80%.In another embodiment, described mixture comprises described (R)-isomer of 90% and described (S)-isomer of 10%.In another embodiment, described mixture comprises described (R)-isomer of 10% and described (S)-isomer of 90%.
In one embodiment, compound of the present invention is SARM.In one embodiment, for example estrogen receptor, PgR or glucocorticoid receptor combine compound of the present invention with nuclear hormone receptor.
The present invention includes " pharmacy acceptable salt " of The compounds of this invention, it can be by compound of the present invention and acid or alkali reaction generation.
The pharmacy acceptable salt of the amine of suitable formula I can be by mineral acid or organic acid preparation.In one embodiment, the example of the inorganic salt of amine is a hydrosulfate, borate, bromide, muriate, Hemisulphate (hemisulfates), hydrobromate, hydrochloride, 2-isethionate (isethionate (hydroxyethanesulfonates)), iodate, iodide, different thiosulphate (isothionates), nitrate, persulphate, phosphoric acid salt, vitriol, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulphonate, haloalkyl sulfonate, halogenated aryl sulfonate), sulfonate and thiocyanate-.
In one embodiment, the example of the organic salt of amine comprises aliphatic category, the alicyclic ring same clan, the fragrance same clan, aromatic-aliphatic (araliphatic) class, the heterocycle same clan, carboxylic-acid and sulfonic acid class organic acid, their example is an acetate, arginine, aspartate, ascorbate salt, adipate, anthranilate, alkanoic acid salt, replace alkanoic acid salt, alginate, benzene sulfonate, benzoate, hydrosulfate, butyrates, supercarbonate, bitartrate, carboxylate salt, Citrate trianion, camphorate (camphorates), camsilate, cyclohexyl-n-sulfonate, cyclopentane propionate, the edetic acid calcium salt, d-camphorsulfonic acid (camsylates), carbonate, the little sour potassium of carat, cinnamate, dicarboxylate, digluconate, dodecane sulfonate, dihydrochloride, caprate, enanthate (enanthuates), esilate, edetate, ethanedisulphonate, Estolate (estolates), esilate, fumarate, formate, fluorochemical, the galacturonic hydrochlorate, gluconate, glutaminate, glycollate (glycolates), gluconate, glucose enanthate (glucoheptanoates), glycerophosphate, gluceptate, to hydroxyl kharophen phenylarsonate (glycollylarsanilates), glutarate, glutaminate, enanthate, hexanoate, hydroxymaleic acid salt, hydroxycarboxylic acid, Sucrets salt (hexylresorcinates), hydroxybenzoate, Hydroxynaphthoate, hydrofluoride (hydrofluorate), lactic acid salt, Lactobionate (lactobionates), lauroleate, malate, maleate, methylene-bis (2-Naphthol hydrochlorate) (methylenebis (beta-oxynaphthoate)), malonate, mandelate, mesylate (mesylates), mesylate (methane sulfonates), MB, methyl nitrate, metilsulfate, the toxilic acid monopotassium salt, mucate, monocarboxylate, naphthalenesulfonate, the 2-naphthalenesulfonate, nicotinate, naphthalenesulfonate, the N-methylglucosamine, barkite, octylate, oleate, embonate, phenylacetate, picrate, phenylbenzoate, Pivalate, propionic salt, phthalate, pectate (pectinates), phenpropionate, palmitate, pantothenate, galactosan aldehydic acid salt (polygalacturates), pyruvate salt, quinate, Whitfield's ointment, succinate, stearate, sulfanilate, subacetate, tartrate, cariamyl (theophyllineacetates), tosilate, trifluoroacetate, terephthalate, tannate, teoclate, three halogenated acetic acids salt, triethiodide, tricarboxylate, undecylate or valerate.
In one embodiment, the example of the inorganic salt of carboxylic acid or phenol comprises ammonium; Basic metal comprises lithium, sodium, potassium, caesium; Alkaline-earth metal comprises calcium, magnesium, aluminium; Zinc, barium, chlorine or quaternary ammonium.
In another embodiment, the example of the organic salt of carboxylic acid or phenol comprises arginine; Organic amine, comprise the aliphatics organic amine, alicyclic organic amine, the aromatic series organic amine, dibenzylethylenediamine dipenicillin G, TERTIARY BUTYL AMINE, Benethamine diacetale (N-benzyl-1-phenylethylamine), dicyclohexylamine, dimethylamine, diethanolamine, thanomin, quadrol, sea crust amine (hydrabamine), imidazoles, Methionin, methylamine, trimeric cyanamide (meglamines), N-methyl D-glycosamine, N, N '-dibenzyl-ethylenediamin, niacinamide, organic amine, ornithine, pyridine, picoline (picolies), piperazine, PROCAINE HCL, PHARMA GRADE, trihydroxymethylaminomethane, triethylamine, trolamine, Trimethylamine 99, tromethane or urea.
In one embodiment, described salt can form by ordinary method, undissolved solvent of for example described therein salt or medium or for example in the solvent of water, make the free alkali of product or free acid form and one or suitable acid or the alkali reaction of many equivalents form, in a vacuum, be that another kind of ion or suitable ion exchange resin are removed described salt by lyophilize or the ion-exchange by the salt that will exist.
In one embodiment, the present invention also comprises the N-oxide compound of the amino substituent of compound described herein.Similarly, can prepare the ester of phenolic compound with aliphatics and aromatic carboxylic acid, for example acetic ester and benzoic ether.
The invention provides the derivative of described compound.In one embodiment, " derivative " includes but not limited to ether derivative, acid derivative, amide derivatives, ester derivative etc.In another embodiment, the present invention also comprises the hydrate of described compound.
In one embodiment, " hydrate " includes but not limited to hemihydrate, monohydrate, dihydrate, trihydrate etc.
In other embodiments, the invention provides the meta-bolites of described compound.In one embodiment, " meta-bolites " refers to any material of being produced by another kind of material by metabolism or metabolic process.
In other embodiments, the invention provides the medicine of described compound.In other embodiments, term " medicine " refers to the composition (pharmaceutical composition) of suitable pharmaceutical applications for example as described herein.
In one embodiment, " alkyl " refers to saturated aliphatic hydrocarbon, comprises straight chain, side chain and cyclic alkyl.In one embodiment, described alkyl has 1-12 carbon atom.In another embodiment, described alkyl has 1-7 carbon atom.In another embodiment, described alkyl has 1-6 carbon atom.In another embodiment, described alkyl has 1-4 carbon atom.Described alkyl can be unsubstituted or is selected from following group and be replaced by one or more: halogen, hydroxyl, carbalkoxy, amide group, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-(thio) and sulfane base.In one embodiment, described alkyl is CH 3
In another embodiment, " thiazolinyl " refers to undersaturated hydrocarbon, comprises straight chain, side chain and cyclic group with one or more pairs of keys.Described thiazolinyl can have two keys, two two keys, three two keys etc.The example of thiazolinyl is vinyl, propenyl, butenyl, cyclohexenyl etc.In one embodiment, described thiazolinyl has 1-12 carbon atom.In another embodiment, described thiazolinyl has 1-7 carbon atom.In another embodiment, described thiazolinyl has 1-6 carbon atom.In another embodiment, described thiazolinyl has 1-4 carbon atom.Described thiazolinyl can be unsubstituted or is selected from following group and be replaced by one or more: halogen, hydroxyl, carbalkoxy, amide group, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-and sulfane base.
" haloalkyl " refers to the alkyl as defined above that replaced by one or more halogen atoms, replaced by F in one embodiment, replaced by Cl in another embodiment, replaced by Br in another embodiment, replaced by I in another embodiment.
" aryl " refers to have the aromatic group of at least one carbocyclic aromatic group or heterocyclic aromatic group, and described aryl can be unsubstituted or is selected from following group and be replaced by one or more: halogen, hydroxyl, carbalkoxy, amide group, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-and sulfane base.The nonrestrictive example of aromatic ring is phenyl, naphthyl, pyranyl, pyrryl, pyrazinyl, pyrimidyl, pyrazolyl, pyridyl, furyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl etc.In one embodiment, described aryl is a 4-8 unit ring.In another embodiment, described aryl is a 4-12 unit ring.In another embodiment, described aryl is 6 yuan of rings.In another embodiment, described aryl is 5 yuan of rings.In another embodiment, described aryl is the condensed ring system of 2-4 ring.
" hydroxyl " refers to the OH base.It should be appreciated by those skilled in the art that when T was OR, R was not OH.
In one embodiment, term " halogen " refers to F in one embodiment, refers to Cl in another embodiment, refers to Br in another embodiment, refers to I in another embodiment.In one embodiment, described optically active (R) isomer or (S) enantiomer comprise crystallization technique from the separation of racemic compound of the present invention.In another embodiment, described crystallization technique comprises the differentiation crystallization (differential crystallization) of enantiomer.In another embodiment, described crystallization technique comprises the differentiation crystallization of diastereomeric salt (tartrate or quinine salt).In another embodiment, described crystallization technique comprises that chirality assists the differentiation crystallization of derivative (menthol ester etc.).In another embodiment, described optically active (R) isomer or (S) enantiomer comprise from the separation of racemic compound of the present invention and make described racemic mixture and the reaction of another kind of chiral radicals, form diastereomeric mixture, separate diastereomer then and remove other chiral radicals to obtain pure enantiomer.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise that from the separation of the racemic mixture of The compounds of this invention chirality is synthetic.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise biological the fractionation from the separation of the racemic mixture of The compounds of this invention.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise that from the separation of the racemic mixture of The compounds of this invention enzyme process splits.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise the chromatographic separation of using chiral stationary phase from the separation of the racemic mixture of The compounds of this invention.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise affinity chromatography from the separation of the racemic mixture of The compounds of this invention.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise capillary electrophoresis from the separation of the racemic mixture of The compounds of this invention.In another embodiment, described optically active (R) isomer or (S) enantiomer comprise the hydroxyl that forms chiral carbon atom and the ester group of optically active acid (for example (-)-dextrocamphoric acid) from the separation of the racemic mixture of The compounds of this invention, by fractional crystallization or preferably separate the ester of thus obtained diastereomer by flash chromatography (flash-chromatography), then that each is independent ester is hydrolyzed to alcohol.
In another embodiment, purity by method of the present invention or the enantiomer that chiral separation obtained by racemic mixture of the present invention and selectivity can be analyzed by HPLC and measure.
In another embodiment, described method also comprises the step that the compound of formula (I) is converted into its isomer, meta-bolites, pharmacy acceptable salt, medicine, N-oxide compound, hydrate or their arbitrary combination.
Should be appreciated that described method can comprise any embodiment as herein described, person of skill in the art will appreciate that, described embodiment can be suitable for preparing the compound of corresponding.
In some embodiments, compound as herein described is used to prevent and the illness and the illness relevant with diabetes for the treatment of muscular atrophy, bone photo pass.
In some embodiments, compound as herein described can be used for the treatment of male with the female relevant illness of various hormones individually or as composition, for example hypogonadism, Sarcopenia, erection problem, shortage sexual desire, osteoporosis and fertilizability (fertility).In some embodiments, compound as herein described is used to stimulate or promotes or recover function to various procedures, this causes treating illness as herein described then, especially comprise promoting erythropoiesis, osteogenesis, muscle growth, glucose uptake, insulin secretion, and/or prevent lipid generation, blood coagulation, insulin resistant, atherosclerosis, osteoclast activity etc.
In one embodiment, method of the present invention utilizes described compound to contact or combination with acceptor, and mediates described effect thus.In some embodiments, described acceptor is a nuclear receptor, in one embodiment, described nuclear receptor is an androgen receptor, perhaps be estrogen receptor in another embodiment, perhaps being PgR in another embodiment, perhaps is glucocorticoid receptor in another embodiment.In some embodiments, described multiple effect can be used as with the function of individual multiple receptors bind and takes place simultaneously.Effect when in some embodiments, the tissue selectivity effect of compound as herein described provides different target organ.
Pharmaceutical composition
In some embodiments, the invention provides the method for use, described method comprises that administration contains described compound compositions.As used herein, " pharmaceutical composition " refers to the activeconstituents (being the compound of formula I) of " treatment significant quantity ", with pharmaceutically acceptable carrier or thinner.As used herein, " treatment significant quantity " refers to provide for given illness and dosage regimen the amount of curative effect.
As used herein, term " administration " instigates individuality to contact with compound of the present invention.As used herein, administration can be carried out in (i.e. for example human cell or tissue of the organism of Huoing) in external (in vitro promptly) or body.In one embodiment, the present invention includes to individual administration compound of the present invention.
The pharmaceutical composition that contains The compounds of this invention can be by any method known to those skilled in the art to individual administration, in for example oral, parenteral, the blood vessel, by the cancer,, in intravenously, intracutaneous, subcutaneous, hypogloeeis, intraperitoneal, the ventricle through mucous membrane, in skin, intramuscular, nose, encephalic, intravaginal administration, by administration in suction, per rectum, the knurl, perhaps can be delivered to any method (for example puncture needle (needle) or conduit) administration of tissue by recombinant virus/composition wherein.Perhaps, for use to mucomembranous cell, skin or eyes use, and may need topical application.The method of another kind of administration is through inhalation or aerosol.
In one embodiment, described drug composition oral administration, so it is formulated into the form that is fit to oral administration, promptly as solid or liquid preparation.Suitable solid orally ingestible comprises tablet, capsule, pill, granule, piller (pellets), powder etc.Suitable liquid oral medicine comprises solution, suspensoid, dispersion agent, emulsion, finish etc.In one embodiment of the invention, described SARM compound is formulated in the capsule.According to this embodiment, composition of the present invention also contains hard capsule except that containing compound of the present invention and inert support or thinner.
In one embodiment; described micronized capsule comprises the particle that contains The compounds of this invention; wherein; term used herein " micronize " refers to that particle diameter is less than 100 microns particle; perhaps in another embodiment; refer to that particle diameter is less than 60 microns particle; perhaps in another embodiment; refer to particle diameter less than 36 microns particle, perhaps in another embodiment, refer to that particle diameter is less than 16 microns particle; perhaps in another embodiment; refer to particle diameter less than 10 microns particle, perhaps in another embodiment, refer to that particle diameter is less than 6 microns particle.
And in another embodiment, described pharmaceutical composition comes administration by intravenously, intra-arterial or intramuscularly liquid preparation.Suitable liquid preparation comprises solution, suspensoid, dispersion agent, emulsion, finish etc.In one embodiment, therefore described pharmaceutical composition is formulated into the form that is fit to intravenous administration through intravenous administration.In another embodiment, therefore described pharmaceutical composition is formulated into the form that is fit to the intra-arterial administration through the intra-arterial administration.In another embodiment, therefore described pharmaceutical composition intramuscular administration is formulated into the form that is fit to intramuscular administration.
And in another embodiment, described pharmaceutical composition is locally applied to body surface, therefore is formulated into the form that is fit to topical application.Suitable topical formulations comprises gelifying agent, ointment, emulsion, lotion, drops etc.For topical application, the derivative that tolerates on compound of the present invention or its physiology (for example salt, ester, N-oxide compound etc.) is formed in solution, suspensoid or emulsion in the physiologically acceptable thinner that has or do not have pharmaceutical carrier, and uses with these forms.
And in another embodiment, described pharmaceutical composition comes administration as suppository (for example rectal suppository or urethral suppositories).And in another embodiment, described pharmaceutical composition comes administration by the subdermal implantation piller.In another embodiment, described piller provides the sustained release of compound described herein in for some time.In another embodiment, described pharmaceutical composition transvaginal administration.
In another embodiment, active compound can in vesicles, particularly liposome, send (referring to Langer, Science 249:1627-1633 (1990); People such as Treat are in Liposomes in theTherapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (author), Liss, New York, pp.363-366 (1989); Lopez-Berestein, ibid, pp.317-327; Usually referring to ibid).
As used herein, " pharmaceutically acceptable carrier or thinner " is well known to those skilled in the art.Described carrier or thinner can be solid carrier or the thinner that is used for solid preparation, the liquid vehicle that is used for liquid preparation or thinner or their mixture.
Solid carrier/thinner includes but not limited to colloid, starch (for example W-Gum, pre-gelatinized starch (pregeletanized starch)), sugar (for example lactose, N.F,USP MANNITOL, sucrose, glucose), cellulose materials (for example Microcrystalline Cellulose), acrylate (for example polymethacrylate), lime carbonate, magnesium oxide, talcum or their mixture.
In one embodiment, composition of the present invention can comprise compound of the present invention or itself and one or more pharmaceutically acceptable vehicle arbitrary combination.
Should be appreciated that, the present invention includes compound described herein any embodiment of (being called as " compound of the present invention " in some embodiments).
According to embodiment of the present invention, suitable vehicle and carrier can be solid or liquid, and its type is generally selected according to the administration type of using.Liposome also can be used to send described composition.The example of suitable solid carrier comprises lactose, sucrose, gelatin and agar.Oral dosage form can contain suitable binder, lubricant, thinner, disintegrating agent, tinting material, seasonings, flow-induction agent (flow-inducing agent) and fusion agent.Liquid dosage form can contain for example suitable solvent, sanitas, emulsifying agent, suspending agent, thinner, sweeting agent, thickening material and fusion agent.Parenteral and intravenously form also should comprise mineral substance and other material so that make that the type of they and selected injection or delivery system is compatible.Certainly, also can use other vehicle.
For liquid preparation, pharmaceutically acceptable carrier can be aqueous or non-aqueous solution, suspension, emulsion or oil.The example of non-aqueous solvent is a for example ethyl oleate of propylene glycol, polyoxyethylene glycol and injectable organosilane ester.Aqueous carrier comprises water, alcohol/aqueous solution, cyclodextrin, emulsion or suspension, comprises salt solution and buffering medium.The example of oil is the oil in oil, animal oil, vegetables oil or synthetic source, for example, and peanut oil, soybean oil, mineral oil, sweet oil, sunflower oil and Oils,glyceridic,cod-liver.
Parenteral carrier (being used for subcutaneous, intravenously, intra-arterial or intramuscularly) comprises sodium chloride solution, woods Ge Shi glucose, glucose and sodium-chlor, lactated Ringer's and fixed oil.Intravenous vehicles comprises fluid and nutritious supplementary, electrolyte replenisher electrolyte replenisher of woods Ge Shi glucose (for example based on) etc.Its example is a sterile liquid, for example adds and do not add the water and the oil of tensio-active agent and other pharmaceutically acceptable auxiliary agent.Usually, water, salt solution, D/W and relevant sugar soln and glycol for example propylene glycol or polyoxyethylene glycol are preferred liquid vehicles, particularly for injectable solutions.The example of oil is the oil in oil, animal oil, vegetables oil or synthetic source, for example, and peanut oil, soybean oil, mineral oil, sweet oil, sunflower oil and Oils,glyceridic,cod-liver.
And, described composition can also comprise tackiness agent (gum arabic for example, W-Gum, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, Vltra tears, polyvidone), disintegrating agent (W-Gum for example, yam starch, alginic acid, silicon-dioxide, croscarmellose sodium (croscarmelose sodium), Crospovidone, guar gum, sodium starch glycollate), the buffer reagent of various pH and ionic strength (Tris-HCl for example, acetate, phosphoric acid salt), prevent to be adsorbed onto surperficial additive for example albumin or gelatin, (for example Tween 20 for washing composition, Tween 80, Pluronic F68, bile salt), proteinase inhibitor, tensio-active agent (for example sodium lauryl sulphate), penetration enhancer, solubilizing agent (cremophor (cremophor) for example, glycerine, polyethylene glycerine (polyethylene glycerol), benzalkonium chloride, peruscabin, cyclodextrin, anhydrosorbitol (sobitan) ester, stearic acid), antioxidant (is an xitix, sodium metabisulfite, butylated hydroxyanisol (butylated hydroxyanisole)), stablizer (hydroxypropylcellulose for example, Vltra tears), viscosity increaser (carbomer for example, colloid silica, ethyl cellulose, guar gum), sweeting agent (aspartame for example, citric acid), sanitas (Thimerosal for example, benzylalcohol, metagin), tinting material, lubricant (stearic acid for example, Magnesium Stearate, polyoxyethylene glycol, sodium lauryl sulphate), glidant (for example colloid silica), softening agent (diethyl phthalate for example, triethyl citrate), emulsifying agent (carbomer for example, hydroxypropylcellulose, sodium lauryl sulphate), polymer coating (for example husky amine (poloxamines) of poloxamer or pool Lip river), Drug coating and membrane-forming agent (ethyl cellulose for example, acrylate, polymethacrylate) and/or assistant agent.
In one embodiment, pharmaceutical composition provided herein is a controlled release composition, and promptly in said composition, compound of the present invention discharged in for some time after administration.Controlled release or slow releasing composition comprise the preparation in the lipotropy storage storehouse (depots) (for example lipid acid, wax, oil).In another embodiment, described pharmaceutical composition is an immediate release composition, i.e. all compound of amount release immediately after administration in said composition.
In another embodiment, described pharmaceutical composition can be sent in controlled release system.For example, described medicament can use venoclysis, implantable osmotic pump, transdermal patch, liposome or other administering mode administration.In one embodiment, can use pump (referring to Langer, supra; Sefton, CRC Crit.Ref.Biomed.Eng.14:201 (1987); People such as Buchwald, Surgery 88:607 (1980); People such as Saudek, N.Engl.J.Med.321:674 (1989)).In another embodiment, can use polymer materials.In another embodiment, controlled release system can be placed near the treatment target (being brain), therefore only need the part of body dose (referring to for example Goodson, in MedicalApplications of Controlled Release, supra, vol.2, pp.116-138 (1984)).In one piece of summary (Science 249:1627-1633 (1990)) of Langer, other controlled release system has been discussed.
Described composition also can be included in polymeric compounds, for example among the particulate preparation of poly(lactic acid), polyglycolic acid, hydrogel etc. or on, or on liposome, micro emulsion, micelle, single or multiple lift vesicles, blood shadow or spheroplast, introduce active material.This composition can influence release rate and the interior clearance rate of body in physical condition, solvability, stability, the body.
The present invention also comprise be aggregated thing (for example husky amine of poloxamer or pool Lip river) and with direct anti-tissue specificity acceptor, part or antigenic antibody coupling or with little composition of the compound of the ligand coupling of tissue specificity acceptor.
The present invention also comprises by water-soluble polymers, for example the multipolymer of polyoxyethylene glycol, polyoxyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline covalently bound and the compound modified.The compound of known described modification demonstrates the blood halflife more much longer than corresponding unmodified compound (people such as Abuchowski, 1981 after intravenous injection; People such as Newmark, 1982; With people such as Katre, 1987).This modification also can increase solubleness, the elimination of described compound in the aqueous solution assembles, improves the physics and the chemical stability of described compound, and reduces the immunogenicity and the reactivity of described compound greatly.Therefore, compare,, can realize the interior biological activity of the body of expecting by the ground of low frequency more or this polymkeric substance-compound derivatives of more low dose of ground administration with the compound of unmodified.
Contain the fine in the art understanding of preparation of drug combination of active ingredient, for example the method by mixing, granulation or compressing tablet.Frequent and the pharmaceutically acceptable and compatible mixed with excipients of active treatment composition with described activeconstituents.For oral administration, the derivative that tolerates on compound of the present invention or their physiology for example salt, ester, N-oxide compound etc. for example carrier, stablizer or inert diluent mix with habitual additive for this purpose, and be converted into the form that is fit to administration with ordinary method, for example tablet, coated tablet, hard or soft capsule, the aqueous solution, alcoholic solution or oily solution.For administered parenterally, the derivative that tolerates on compound of the present invention or their physiology for example salt, ester, N-oxide compound etc. is converted into solution, suspensoid or emulsion (if desired, with habitual, suitable material for this purpose, solubilizing agent etc. for example).
The form that active ingredient can be used as the neutral pharmacy acceptable salt is formulated into composition.Pharmacy acceptable salt comprises acid salt (free amino group by polypeptide or antibody molecule forms), its by mineral acid for example hydrochloric acid or phosphoric acid or organic acid for example acetate, oxalic acid, tartrate, amygdalic acid etc. form.The salt that is formed by free carboxyl group also can derive from mineral alkali, for example sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ironic hydroxide, and organic bases, for example Isopropylamine, Trimethylamine 99,2-ethylamino-ethanol, Histidine, PROCAINE HCL, PHARMA GRADE etc.
In order to be used for medicine, the salt of described compound is pharmacy acceptable salt.But other salt also can be used in the preparation of The compounds of this invention or its pharmacy acceptable salt.The pharmacy acceptable salt of suitable The compounds of this invention comprises acid salt, it can form by for example the solution of The compounds of this invention being mixed with the solution of pharmaceutically acceptable acid, and described acid is hydrochloric acid, sulfuric acid, methylsulfonic acid, fumaric acid, toxilic acid, succsinic acid, acetate, phenylformic acid, oxalic acid, citric acid, tartrate, carbonic acid or phosphoric acid for example.
In one embodiment, the invention provides the pharmaceutical composition that comprises compound of the present invention.In one embodiment, this composition is used for oral testosterone alternative medicine.
In one embodiment, the present invention also provides the composition that comprises two or more compounds of the present invention or their polymorphic form, isomer, hydrate, salt, N-oxide compound etc.The invention still further relates to composition and pharmaceutical composition, described pharmaceutical composition comprises compound of the present invention separately, perhaps comprise compound of the present invention and progestogen or estrogenic combination, perhaps in another embodiment, comprise the combination of the medicament of compound of the present invention and chemotherapy compound, skeletonization compound or myogenic compound or other suitable application as herein described.In one embodiment, composition of the present invention comprises suitable carriers, thinner or salt.
In one embodiment, method of the present invention can comprise with various dosed administrations formula I compound of the present invention.In one embodiment, with 0.1-200mg/ days dosed administration compound of the present invention.In one embodiment with the dosage of 0.1-10mg, or in another embodiment with the dosage of 0.1-26mg, or in another embodiment with the dosage of 0.1-60mg, or in another embodiment with the dosage of 0.3-16mg, or in another embodiment with the dosage of 0.3-30mg, or in another embodiment with the dosage of 0.6-26mg, or in another embodiment with the dosage of 0.6-60mg, or in another embodiment with the dosage of 0.76-16mg, or in another embodiment with the dosage of 0.76-60mg, or in another embodiment with the dosage of 1-6mg, or the dosage of 1-20mg in another embodiment, or in another embodiment with the dosage of 3-16mg, or in another embodiment with the dosage of 30-60mg, or in another embodiment with the dosage of 30-76mg, or in another embodiment with the dosed administration of 100-2000mg compound of the present invention.
In one embodiment, method of the present invention can comprise with various dosed administrations formula I compound of the present invention.In one embodiment, with the dosed administration of 1mg compound of the present invention.In another embodiment, with the dosed administration of 3mg, 6mg, 10mg, 16mg, 20mg, 26mg, 30mg, 36mg, 40mg, 46mg, 50mg, 56mg, 60mg, 66mg, 70mg, 76mg, 80mg, 86mg, 90mg, 96mg or 100mg compound of the present invention.
In one embodiment, the invention provides using method, this method comprises that administration comprises the pharmaceutical composition of and the following: a) compound of any embodiment as herein described; And b) pharmaceutically acceptable carrier or thinner; Described composition is interpreted as comprising analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, N-oxide compound, hydrate or their arbitrary combination of compound described herein, and can comprise the compound of formula I.
In some embodiments, the invention provides the using method of pharmaceutical composition, this pharmaceutical composition comprises: a) compound of any embodiment as herein described comprises its analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, N-oxide compound, hydrate or their arbitrary combination; B) pharmaceutically acceptable carrier or thinner; C) glidant; And d) lubricant.
In another embodiment, the invention provides the using method of pharmaceutical composition, this pharmaceutical composition comprises: a) compound of any embodiment as herein described comprises its analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, N-oxide compound, hydrate or their arbitrary combination; B) Spherolac 100; C) Microcrystalline Cellulose; D) Magnesium Stearate; And e) colloid silica.
In some embodiments, method utilization of the present invention comprises compound compositions of the present invention, and the advantage of described method is that described compound is the non-steroid part of androgen receptor and demonstrates anabolic activity in vivo.According to this aspect, this compound is without severe side effect, administering mode of providing convenience and lower production cost, but and oral biological utilisation, do not have significant cross reactivity with other undesirable steroid receptor, and may have very long biological half-life.
When being applied to Mammals, man-hour particularly estimates that the doctor can determine the actual dose and the treatment time of suitable individuality, and can and reply according to age, the body weight of concrete individuality and change.
In one embodiment, the composition that is used for administration can be the sterile solution agent, perhaps in other embodiments, can be moisture or non-aqueous solution, suspensoid or emulsion.In one embodiment, described composition can comprise propylene glycol, polyoxyethylene glycol, injectable organic ester for example ethyl oleate or cyclodextrin.In another embodiment, composition also can comprise wetting agent, emulsifying agent and/or dispersion agent.In another embodiment, described composition also can comprise sterilized water or any other sterile injectable medium.
In one embodiment, the invention provides compound and the composition (comprising any embodiment as herein described) that is used for any method of the present invention as described herein.In one embodiment, the composition that uses compound of the present invention or contain it can help suppressing, suppress, strengthening or promote desired replying in the individual body, and this point person of skill in the art will appreciate that.In another embodiment, described composition can also contain other activeconstituents, its activity to administration compound of the present invention at concrete application be useful.
In some embodiments, method utilization of the present invention contains compound compositions of the present invention, and the advantage of described method is that described compound is the non-steroid part of androgen receptor and demonstrates anabolic activity in vivo.According to this aspect, this compound is without severe side effect, administering mode of providing convenience and lower production cost, but and oral biological utilisation, do not have significant cross reactivity with other undesirable steroid receptor, and may have very long biological half-life.
When being applied to Mammals, man-hour particularly estimates that the doctor can determine the actual dose and the treatment time of suitable individuality, and can and reply according to age, the body weight of concrete individuality and change.
In one embodiment, the composition that is used for administration can be the sterile solution agent, perhaps in other embodiments, can be water-based or nonaqueous solvent, outstanding mixture or emulsion.In one embodiment, described composition can comprise propylene glycol, polyoxyethylene glycol, injectable organic ester for example ethyl oleate or cyclodextrin.In another embodiment, composition also can comprise wetting agent, emulsifying agent and/or dispersion agent.In another embodiment, described composition also can comprise sterilized water or any other sterile injectable medium.
In one embodiment, the invention provides compound and the composition (comprising any embodiment as herein described) that is used for any method of the present invention as described herein.In one embodiment, the composition that uses compound of the present invention or contain it can help suppressing, suppressing and removes, strengthens or promote desired replying in the individual body, and this point person of skill in the art will appreciate that.In another embodiment, described composition can also contain other activeconstituents, its activity to administration compound of the present invention at concrete application be useful.
In some embodiments, described composition also contains 5 inhibitor (5ARI), one or more SARM, selective estrogen receptor modulators (SERM), aromatase inhibitor (such as, but be not limited to Anastrozole (anastrazole), Exemestane or letrozole), GnRH agonist or antagonist, steroid or on-steroidal GR part, steroid or on-steroidal PR part, steroid or on-steroidal AR part, 17-aldehyde ketone reductase inhibitor or 17beta-Hydroxysteroid dehydrogenase inhibitor.In some embodiments, this composition can be used for the treatment of the hormonal dependent illness, and for example sterile, hormone response cancer is the tumorigenesis of gonadal carcinoma or apparatus urogenitalis cancer for example.
In some embodiments, described composition comprises compound as herein described and another kind of therapeutic compound, especially comprises 5ARI, for example finasteride, dutasteride, izonsteride; Other SARM, for example, RU-58642, RU-56279, WS9761A and B, RU-59063, RU-58841, bexlosteride, LG-2293, L-245976, LG-121071, LG-121091, LG-121104, LGD-2226, LGD-2941, LGD-3305, YM-92088, YM-175735, LGD-1331, BMS-357597, BMS-391197, S-40503, BMS-482404, EM-4283, EM-4977, BMS-564929, BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088, YM-580, LG-123303, LG-123129, PMCol, YM-175735, BMS-591305, BMS-591309, BMS-665139, BMS-665539, CE-590,116BG33,154BG31, arcarine, ACP-105; SERM, for example, tamoxifen (tamoxifene), 4-hydroxyl tamoxifen, idoxifene, toremifene, Ao Peimifen (ospemifene), droloxifene, Reynolds former times sweet smell, arzoxifene, WAY 140424 (bazedoxifene), PPT (1,3,5-three (4-hydroxy phenyl)-4-propyl group-1H-pyrazoles), DPN (diaryl propionitrile), Lasofoxifene, piperazine spray former times sweet smell (pipendoxifene), EM-800, EM-652, nafoxidine, zindoxifene, Tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780, Clomiphene, MER-25, diethylstilbestrol, coumestrol, genistein, GW5638, LY353581, zuclomifene, Enclomifene (enclomiphene), delmadinone acetate, DPPE, (N, N-diethyl-2-{4-(phenyl methyl)-phenoxy group } ethamine), TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, Pu Linbeirui (prinaberel), ERB-041, WAY-397, WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, [18F] FEDNP, LSN-500307, AA-102, Herba Scutellariae Barbatae (Ban zhi lian), CT-101, CT-102, VG-101; GnRH agonist or antagonist, for example, Leuprolide, goserelin, triptorelin, alfaprostol, histrelin, detirelix, Ganirelix, peace peptide iturelix, cetrorelix, ramorelix, Ganirelix, Antarelix, Teverelix, abarelix, difficult to understandly prick Rake (ozarelix), relax cut down Ge Ruike (sufugolix), prazarelix, add Rake (degarelix), NBI-56418, TAK-810, fatty acyl group alkali (acyline); FSH agonist or antagonist, LH agonist/antagonist, aromatase inhibitor, for example letrozole, Anastrozole, Atamestane, fadrozole, minamestane, Exemestane, plomestane, liarozole, NKS-01, vorozole, YM-51, finrozole, 4-hydroxyandrostenedione, aminoglutethimide (aminogluethimide), Rogletimide; Steroid or on-steroidal glucocorticoid receptor ligands, for example, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mifepristone, RPR-106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-394531, A-222977, AL-438, A-216054, A-276575, CP-394531, CP-409069, UGR-07; Steroid or on-steroidal PgR part; Steroid or on-steroidal AR antagonist, for example flutamide, Sch 16423, bicalutamide, Nilutamide, hydroxysteroid dehydrogenase inhibitors, the PPAR alpha ligands is bezafibrate, fenofibrate, gemfibrozil for example; PPAR γ part, for example, darglitazone, pioglitazone, rosiglitazone, Netoglitazone (isaglitazone), Li Gelie ketone (rivoglitazone), netoglitazone (netoglitazone); The PPAR part of dual function for example, naveglitazar, farglitazar, is pricked (ragaglitazar), Ao Geliezha (oxeglitazar), PN-2034, PPAR δ for Ge Liezha (tesaglitazar), glug row; The 17-KR inhibitor, 3 β-DH Δ 4,6-isomerase inhibitors, 3 β-DH Δ 4,5-isomerase inhibitors, 17,20 desmolase inhibitor, p450c17 inhibitor, p450ssc inhibitor, 17,20 lyase inhibitor, or their combination.
Should be appreciated that any method of above two or more medicaments of administration, timing, approach or their combination should be considered to be comprised by phrase as herein described " Combined Preparation ".
In one embodiment, its risk is suffered from treatment, prevention, compacting or the inhibition or the reduction that the invention provides the bone dependent event (SRE) of suffering from the cancer individuality, it comprises administration compound as herein described and/or its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination, and described bone dependent event (SRE) is fracture, osseous surgery, bone radiation, compressive myelopathy, area of new bone transfer, bone loss or their combination for example.The present invention be more particularly directed to carrying out or carrying out the SRE that suffers from the prostate cancer individuality of androgen-deprivation treatment (ADT) with the compounds for treating of formula (I).
In one embodiment, with method provided herein and/or to utilize the bone dependent event of combination treatment provided herein be fracture, in one embodiment, described fracture is pathologic fracture, atraumatic fracture, spinal fracture, non-spinal fracture, somatometry of physique fracture (morphometricfractures) or their combination.In some embodiments, fracture can be closed fracture, compound fracture, transverse fracture, greenstick fracture or comminuted fracture.In one embodiment, what fracture took place can be any bone of health, and in one embodiment, described fracture is arm, wrist, hand, refer to, the fracture in any one or more bone of leg, ankle, foot, toe, hip, clavicle or their combination.
In another embodiment, method provided herein and/or composition are treated, prevent, suppress, are suppressed the bone dependent event effectively or reduce its risk, described bone dependent event pain that for example pathologic fracture, compressive myelopathy, hypercalcemia are many, bone photo closes or their combination.
In another embodiment, make every effort to method provided herein and/or utilize the bone dependent event of combination treatment provided herein to comprise necessary osseous surgery and/or bone radiation, it is used for the treatment of the pain that is caused by bone infringement or neurothlipsis in one embodiment in some embodiments.In another embodiment, make every effort to method provided herein and/or utilize the bone dependent event of combination treatment provided herein to comprise individual compressive myelopathy, or be necessary to change antitumor therapy, comprise the change hormonotherapy.In some embodiments, make every effort to method provided herein and/or utilize the bone dependent event of combination treatment provided herein to comprise treatment, compacting, prevention bone transfer or bone loss, reduce its sickness rate or delay its progress or seriousness.In one embodiment, bone loss can comprise osteoporosis, osteopenia or their combination.In one embodiment, the bone dependent event can comprise the arbitrary combination of the embodiment that this paper is listed.
In one embodiment, method provided herein and/or utilize composition provided herein to reduce bone effectively and shift is for example in focus quantity, focus size or their combined aspects.According to this aspect of the invention, in one embodiment, this paper provides a kind of prevention or suppresses the method that individual cancer shifts to bone, the described step that comprises the composition of toremifene, raloxifene, tamoxifen or its analogue, functional deriv, meta-bolites or their combination or their pharmacy acceptable salt to described individual administration that comprises.In one embodiment, described meta-bolites can comprise Ao Peimifen, fispemifene (fispemifene) or their combination.In one embodiment, described cancer is a prostate cancer.
In one embodiment, the described bone dependent event result that is cancer therapy.In one embodiment, described bone dependent event is the result that hormone is deprived treatment, and in another embodiment, they are results of androgen-deprivation treatment (ADT).
In one embodiment, compound of the present invention is used for prevention or reverses the side effect that androgen-deprivation treatment (ADT) causes, for example muscle mass minimizing, muscle strength reduction, fragility, hypogonadism, osteoporosis, osteopenia, BMD reduce and/or the bone amount reduces.
Male, although the descending naturally of ripening stage sexual hormoue (male sex hormone directly reduce and by androgenic periphery aromizing produce estrogenic low-level) relevant with the bone fragility, this effect is male more obvious what accepting that androgen-deprivation treats.
In some embodiments, arbitrary composition of the present invention comprises the formula I compound in any embodiment arbitrary form or as herein described.In some embodiments, arbitrary composition of the present invention is made up of formula I compound arbitrary form or in any embodiment as herein described.In some embodiments, arbitrary composition of the present invention mainly is made up of the compound of formula I arbitrary form or in any embodiment as herein described.In some embodiments, term " comprises " promoting agent (for example compound of formula I) that refers to comprise indication and comprises known other promoting agent and pharmaceutically acceptable carrier in the pharmaceutical industries, vehicle, lubricant, stablizer etc.In some embodiments, term " mainly by ... form " refer to such composition, its unique activeconstituents is the activeconstituents of indication, but, other compound that can comprise stable, the preservation that is used for preparation etc., but described other compound is not participated in the curative effect of the activeconstituents of indication directly.In some embodiments, term " mainly by ... form " can refer to promote the component of the release of described activeconstituents.In some embodiments, term " by ... form " refer to contain the composition of described activeconstituents and pharmaceutically acceptable carrier or vehicle.
In one embodiment, the invention provides combined preparation.In one embodiment, term " combined preparation " is defined as " medicine box (kit of parts) " especially, its meaning is the combination partner administration independently as above definition, the different fixing composition administration that perhaps has the combination partner of different amounts by use, i.e. administration side by side, concomitantly, respectively or in turn.So, in some embodiments, the parts of described medicine box are administration simultaneously for example, perhaps in chronological sequence replaces (promptly for any parts of medicine box at different time points, with the identical or different timed interval) administration.In some embodiments, can control the ratio of the total amount of the combination partner in the described combined preparation.In one embodiment, for example for the needs of tackling part patient subgroups to be treated or the needs of single patient, described combination preparation can change, described different needs may be owing to disease specific, described severity of disease, age, sex or body weight, and this can easily be determined by those skilled in the art.
Should be appreciated that, the present invention relates to be used for the composition as herein described and the conjoint therapy of any suitable disease, obstacle or illness, persons skilled in the art will recognize that this point.Above narrated some application of described composition and conjoint therapy to specified disease, obstacle and illness, they represent embodiment of the present invention, and by representing other embodiment of the present invention separately or as the method that the part of described conjoint therapy is come administration compound as herein described or used composition of the present invention to treat individual described disease, obstacle and illness.
The biological activity of selective androgen conditioning agent compound
In some embodiments, compound of the present invention can be used for oral testosterone alternative medicine.In other embodiments, the compound that suitably replaces is used for: a) male contraception; B) the relevant illness of the various hormones of treatment, for example relevant illness, for example fatigue, depression, sexual desire reduction, sexual dysfunction, erective dysfunction, hypogonadism, osteoporosis, alopecia, obesity, Sarcopenia, osteopenia, benign prostatic hyperplasia and mood and cognitive change with ADAM; C) the treatment illness relevant, for example sexual dysfunction, sexual desire reduction, hypogonadism, Sarcopenia, osteopenia, osteoporosis, cognition and emotional change, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer with ADIF; D) treat and/or prevent chronic myatrophy; E) treatment prostate cancer, prostate cancer imaging, reduce prostate cancer sickness rate, make its termination or cause it to disappear; F) treatment type i diabetes; G) treatment type ii diabetes; H) compacting or suppress diabetes or reduce its sickness rate; I) treatment glucose intolerance; J) treatment hyperinsulinemia; K) treatment insulin resistant; L) treatment diabetic nephropathy; M) treatment diabetic neuropathy; N) treatment of diabetic retinopathy becomes; O) treatment fatty liver disease; P) treatment emaciation; Q) oral androgenic substitutes and/or other clinical treatment and/or diagnostic field, comprises any embodiment that term as herein described " treatment " is included.
In some embodiments, compound of the present invention has tissue selectivity androgenic activity and anabolic activity in vivo, therefore, can be used for concrete application, and those skilled in the art club recognizes this point.
In one embodiment, the invention provides: a) method of the individuality of muscular atrophy is suffered from treatment; B) method of underfed individuality is suffered from treatment; C) method of the bone photo related disorders of treatment individuality; D) method of the individual bone amount of increase; E) method of the individual lipid profile of improvement; F) method of treatment atherosclerosis and relative disease thereof; G) improve the individual handiness and the method for motion; H) method of the individuality of nanism is suffered from treatment; I) method of the individuality of dysmenorrhoea is suffered from treatment; J) method of the individuality of psychologic dyspareunia is suffered from treatment; K) method of the individuality of dysspermatogenic sterility is suffered from treatment; These methods comprise to the analogue of the compound of described individual Medicine-feeding type I and/or described compound, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, impurity or crystal or their arbitrary combination.
In some embodiments, compound as herein described and/or the composition that comprises them can be used for the disease that various application and treatment wherein need to improve depressed or other neuroprotective of cognition, minimizing or treatment.
In one embodiment, " cognition " points out the process of knowledge, particularly keeps the process of clear-headed, understanding, thinking, study and judgement.Cognition relates to psychology, linguistics, computer science, neuroscience, mathematics, ethology and philosophy field.In one embodiment, " mood " refers to the temper or the mental status.As referred to herein, change point out know and/or mood any actively or passive the variation.
In one embodiment, the disease of " depression " reference and health, mood and thinking, it influences mode, the mode of self-perception and the mode of consideration things that the people has a meal, sleeps.Depressed S﹠S comprise shortage activity interest, anorexia or excessive eating, shortage expression, hollow, sensation is desperate, pessimistic, guilty or helpless, (social withdrawal), fatigue, somnopathy are shunk back in social activity, concentrate, remember or make decision difficult, restless, irritability, headache, gastricism or chronic pain.
In one embodiment, method of the present invention is used for individuality, and it is human.In another embodiment, described individuality is a Mammals.In another embodiment, described individuality is an animal.In another embodiment, described individuality is an invertebrates.In another embodiment, described individuality is a vertebrates.
In one embodiment, described individuality is male.In another embodiment, described individuality is male.In some embodiments, male and female although method as herein described can be used for the treatment of,, as described herein and given an example, for some method, female administration of more advantageously replying some compound.
In some embodiments, male and female although method as herein described can be used for the treatment of,, as described herein, for some method, male administration of more advantageously replying some compound.
In some embodiments, compound as herein described and/or the composition that comprises them can be used for the application or the treatment of and the following: alopecia (hair loss), alopecia (alopecia), androgenetic alopecia, alopecia areata, the chemotherapeutic alopecia of secondary, the radiotherapeutic alopecia of secondary, by the alopecia of cicatrization inductive or by the alopecia of stress-induced.In one embodiment, " alopecia (hair loss) " or " alopecia (alopecia) " refer to the alopecia as the male pattern alopecia of utmost point general types.Alopecia is begun by the patch alopecia of scalp usually, be developed to whole alopecia sometimes, even chaeta comes off.Alopecia had both influenced the male sex and had also influenced the women.
In some embodiments, compound as herein described and/or the composition that comprises them can be used for the application and the treatment of disease or the illness relevant with the individuality of suffering from anaemia.In one embodiment, " anaemia " refers to have less than the normal quantity of red blood cell in the blood or less than the normal amount of oxyphorase in the blood, the illness that hematocrit reduces or on average blood cell volume reduces or the hemocyte size reduces.When anaemia, the oxygen carrying capacity of blood descends.In some embodiments, the treatment anaemia also can refer to treat the latency that causes anaemia in this article, for example: a) hemorrhage; B) haemolysis (red blood cell excessively destroys); C) red blood cell produces not enough; And d) Hb A hemoglobin adult deficiency.In some embodiments, treatment anaemia of the present invention refers to treat any form of anaemia, comprises aplastic anemia, benzolism, Fanconi anemia, hemolytic disease of newborn, hereditary spherocytosis, hypoferric anemia, osteoporosis, pernicious anemia, aplastic anemia, hemolytic anemia, sicklemia, renal anemia, thalassemia, myelodysplastic syndrome and various bone marrow disease.
In some embodiments, compound as herein described and/or the composition that comprises them can be used for and individual sexual desire problem or the individual erective dysfunction diseases associated and/or the application and/or the treatment of illness.In one embodiment, " sexual desire " can refer to sexual instinct.
In one embodiment, term " erection " refers to erect or axial ability.Erectile tissue is the also tissue of hardening that can greatly expand by the expansion of its a large amount of blood vessels that contain.
In another embodiment of the invention, be provided for the method for the hormonotherapy of individuality (promptly suffering from the individuality of androgen-dependent illness), described method comprises androgen receptor and compound of the present invention and/or on-steroidal agonist and/or its analogue that makes the patient, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, hydrate, the step of N-oxide compound or the contact of their arbitrary combination, the amount of above-claimed cpd make it combine with described androgen receptor effectively and realize changing the androgen-dependent illness.
In one embodiment of the invention, be provided for the method for patient's (promptly suffering from the individuality of androgen-dependent illness) hormone replacement therapy, described method comprises to individual administration is enough to realize to change the compound as herein described of amount of hormonal dependent illness of described individuality and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, hydrate, N-oxide compound or their arbitrary combination.
Can be with compound as herein described and/or composition, the androgen-dependent illness that comprises method treatment of the present invention comprises and aging, hypogonadism, Sarcopenia, erythropoiesis minimizing, osteoporosis and relevant other illness arbitrarily is correlated with low male sex hormone (for example testosterone) or estrogen level illness.
Can be with compound as herein described and/or composition, the androgen-dependent illness that comprises method treatment of the present invention can comprise that raising with male sex hormone or estrogen level is the illness of feature, comprise hirsutism, sterile, polycystic ovarian syndrome, carcinoma of endometrium, mammary cancer, male pattern alopecia, prostate cancer, carcinoma of testis etc., those skilled in the art can know this point.For these illnesss, can person of skill in the art will appreciate that this point to described individuality individually or unite other therapeutical agent administration compound as herein described.
In one embodiment, the invention provides the individual cancer of treatment, reduce its sickness rate, seriousness or morbidity, delay its progress, prolong remission or delay the method for its outbreak, described method comprises the step to described individual administration compound as herein described and/or its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, hydrate, N-oxide compound or their arbitrary combination.In some embodiments, these cancers are hormonal dependent or androgen receptor dependent tumors (pernicious or benign), for example prostate cancer, ovarian cancer, mammary cancer, uterus carcinoma or carcinoma of testis etc. relevant with male or female germinal tissue.
In some embodiments, the invention provides the method for the treatment of individual cancer preceding omen or pathology, reducing its sickness rate, described method comprises the step to described individual administration compound as herein described and/or its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, hydrate, N-oxide compound or their arbitrary combination.In some embodiments, omen is to see the androgen receptor dependent tumors in the hormone response tissue or for example prostate gland, ovary, mammary gland, uterus or testis etc. are relevant with male or female germinal tissue before these cancers.In some embodiments, omen comprises for example any partial upward intracutaneous tumor-like lesion of prostate gland, uterine cervix etc. before these cancers.In some embodiments, this method is used for the treatment of knurl or tumour early stage, heteroplasia or the hyperplasia in the tissue of for example male or female reproductive tissue.
In one embodiment, the invention provides compound, composition and/or their using method in treatment benign prostatic hyperplasia (BPH)." BPH (benign prostatic hyperplasia) " is prostatic optimum increase, and it is the prevailing hyperplasia of prostate sexual abnormality of finding in any internal organs, and be adult man morbidity main diseases because of.The male sex greater than 50 years old above 75% suffers from BPH, and in 90 years old the male sex, its morbidity reaches 88%.BPH often causes pushing gradually and passes prostatic urethra part (prostate-urethra).Because the incomplete emptying and the urgent urination of bladder, this causes patient's frequent micturition anxious.The blocking of urine stream also can cause general urinate out of control, comprise and start difficulty when wishing to urinate when urinating and stop urine stream difficulty (a kind of illness that is called overflow incontinence (overflow urinaryincontinence), it can cause urinary tract obstruction and uropoiesis depletion (urinary failure)) because can not and cause from bladder emptying urine.
In one embodiment of the invention, the method for the individual benign prostatic hyperplasia (BPH) of treatment comprises to described individual the administration effectively compound as herein described of the amount of the BPH of the described individuality of treatment and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, hydrate, N-oxide compound or their arbitrary combination.
In some embodiments, the invention provides that compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination are used for the treatment of individual emaciation and/or with the emaciation of related to cancer, alleviate its seriousness, reduce its sickness rate or reduce the using method of its morbidity.In another embodiment, described cancer comprises adrenocortical carcinoma, the rectum cancer, bladder cancer, brain tumor, brain stem glioma, brain tumor, cerebellar astrocytoma, big cerebral astrocytoma (cerebral astrocytoma), ependymoma, medulloblastoma, original neuroectodermal tumor on the curtain (supratentorial primitiveneuroectodermal), pinealoma, the hypothalamus glioma, mammary cancer, carcinoid tumor, cancer, cervical cancer, colorectal carcinoma, colorectal cancer, carcinoma of endometrium, the esophageal carcinoma, cholangiocarcinoma, Juventus family tumor (ewings family of tumors) (Pnet), the outer protoblast tumour of cranium, cancer eye, the intraocular melanoma, carcinoma of gallbladder, cancer of the stomach, blastoma, the outer tumour of sexual gland, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet-cell carcinoma, laryngocarcinoma, leukemia, acute lymphoblastic leukemia, oral carcinoma, liver cancer, lung cancer, nonsmall-cell lung cancer, small cell lung cancer, the lymphoma that AIDS is relevant, central nervous system (primary) lymphoma, cutaneous T cell lymphoma, lymphoma (Hodgkin's disease and non-Hodgkin lymphoma), malignant mesothe, melanoma, the Merkel cell carcinoma, transitivity squama cancer, multiple myeloma, plasmoma, mycosis fungoides, myelodysplastic syndrome, myeloproliferative diseases, nasopharyngeal carcinoma, neuroblastoma, the oropharynx cancer, osteosarcoma, ovarian epithelium sample cancer, ovarian germ cell tumors, ovary hangs down pernicious potential tumor, exocrine pancreas cancer (exocrine pancreatic cancer), islet-cell carcinoma, carcinoma of the pancreas, paranasal sinus and CARCINOMA OF THE NASAL CAVITY, parathyroid carcinoma, penile cancer, the pheochromocytoma cancer, the hypophysis cancer, plasmoma, prostate cancer, rhabdosarcoma, the rectum cancer, renal cell carcinoma, salivary gland carcinoma, Sezary syndrome, skin carcinoma, cutaneous T cell lymphoma, Kaposi sarcoma, melanoma, carcinoma of small intestine, soft tissue sarcoma, soft tissue sarcoma, carcinoma of testis, malignant thymoma, thyroid carcinoma, urethral carcinoma, uterus carcinoma, sarcoma, childhood unusual cancer, carcinoma of vagina, carcinoma vulvae, the nephroblastoma or their arbitrary combination.
In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination is used for the treatment of lung cancer, alleviates its seriousness, reduces its sickness rate or delays the purposes of its outbreak.
In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination is used for the treatment of nonsmall-cell lung cancer, alleviates its seriousness, reduces its sickness rate or delays the purposes of its outbreak.
In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination is used for the treatment of Hodgkin's disease (non-Hodgkin lymphoma perhaps in another embodiment), alleviates its seriousness, reduces its sickness rate or delays the purposes of its outbreak.
In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination is used for the treatment of colorectal cancer, alleviates its seriousness, reduces its sickness rate or delays the purposes of its outbreak.
In some embodiments, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination is used for the treatment of cancer, alleviates its seriousness, reduces its sickness rate or reduces the purposes of its morbidity.In another embodiment, described cancer comprises male sex hormone AR dependent tumors (pernicious or benign), for example prostate cancer, mammary cancer (sex, feasible operation or inoperable).In another embodiment, the adjuvant (adjunct) that described SARM compound is ADT, described ADT is used for the treatment of prostate cancer, bladder cancer, the cancer of the brain, bone tumor, colorectal carcinoma, carcinoma of endometrium, liver cancer, lung cancer, lymphatic cancer, kidney, osteosarcoma cancer, ovarian cancer, carcinoma of the pancreas, penile cancer, skin carcinoma, thyroid carcinoma and/or hormonal dependent cancer.
In one embodiment, the invention provides the following purposes of compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination: a) illness of treatment bone photo pass; B) illness of prevention bone photo pass; C) illness of compacting bone photo pass; D) suppress the illness that bone photo closes; E) increase individual bone strength; F) increase individual bone amount; G) suppress the purposes that osteoclast forms.
In one embodiment, the invention provides the following purposes of compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination: a) accelerated bone reparation; B) treatment bone disorders; C) the treatment bone density reduces; D) the low bone mineral density (BMD) of treatment; E) treatment bone amount reduces; F) treatment metabolism osteopathy; G) promote osteogenesis or regeneration; H) promote bone recovery; I) promote fracture repair; J) promote bone to rebuild; K) the bone infringement after the treatment plastic surgery (comprising face, hip or joint); L) improve bone strength and function; M) increase the cortex of bone amount; N) increase the girder connectivity.
In one embodiment, the illness that described bone photo closes is the heredity illness, in another embodiment, is the treatment plan inductive result by specified disease.For example, in one embodiment, compound as herein described is used for the treatment of the illness of the bone photo pass that is caused to the bone transfer by cancer, or in another embodiment, treatment is for example by giving the illness that androgen-deprivation is treated the bone photo pass of replying individual prostate gland carcinogenesis and causing.
In one embodiment, the described bone photo illness of closing is an osteoporosis.In another embodiment, the described bone photo illness of closing is an osteopenia.In another embodiment, the described bone photo illness of closing is that bone resorption increases.In another embodiment, the described bone photo illness of closing is a fracture.In another embodiment, the described bone photo illness of closing is the bone fragility.
In another embodiment, the described bone photo illness of closing is that bone mineral density (BMD) is lost.In another embodiment, the described bone photo illness of closing is the arbitrary combination that osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility and BMD lose.Every kind of illness is represented independently embodiment of the present invention.
In one embodiment, " osteoporosis " refers to because bone attenuation that the consumption of calcium and bone protein causes and bone amount reduce.In another embodiment, osteoporosis is the skeletal diseases of general, it is characterized in that the bone amount is low, osseous tissue is degenerated, and causes the fragile and fracture susceptibility increase of bone thus.In patients with osteoporosis, bone strength is unusual, in one embodiment, follows the risk of bone fracture that causes thus to increase.In another embodiment, osteoporosis makes usually calcium in seeing bone and protein collagen run off, and in one embodiment, this causes the unusual or bone density decline of bone character.In another embodiment, be subjected to bone that osteoporosis influences can be only owing to not causing slightly falling or damaging and fracture of fracture usually.In one embodiment, fracture can be the form (as in hip fracture) of fissure fracture or the form (as in the vertebra compression fracture) of compression fracture.Backbone, hip and wrist are the common positions that osteoporosis is brought out fracture, and still, fracture also can betide other skeletal sites.In another embodiment, unchecked osteoporosis can cause change, body abnormality and the handiness of position to descend.
In one embodiment, described osteoporosis is caused by androgen-deprivation.In another embodiment, described osteoporosis takes place behind androgen-deprivation.In another embodiment, described osteoporosis is a primary osteoporosis.In another embodiment, described osteoporosis is a secondary osteoporosis.In another embodiment, described osteoporosis is a post-menopausal osteoporosis.In another embodiment, described osteoporosis is osteoporosis childhood.In another embodiment, described osteoporosis is an idiopathic osteoporosis disease.In another embodiment, described osteoporosis is a senile osteoporosis.
In another embodiment, described primary osteoporosis is an I type primary osteoporosis.In another embodiment, described primary osteoporosis is an II type primary osteoporosis.Every type osteoporosis representative independently embodiment of the present invention.
According to this aspect of the invention, in one embodiment, with the illness of compound as herein described or the described bone photo of its combined therapy pass.In another embodiment, before administration one or more compounds as herein described, simultaneously or afterwards, can offer individual other bone and promote property compound.In one embodiment, described bone promotes the property compound can comprise natural or the synthetic material.
In one embodiment, described bone promotion property compound can comprise bone morphogenetic protein (BMP); Somatomedin, for example Urogastron (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF); Hedgehog albumen (for example sonic hedgehog, indian hedgehog and desert hedgehog); Hormone, for example follicle stimulating hormone, parathyroid hormone, parathyroid hormone-related peptide, activator, statin, folliculus chalone, frizzled albumen, frzb albumen or frazzled albumen; BMP is conjugated protein, for example notochord albumen and Pp63 glycophosphoproteins; Cytokine, for example IL-3, IL-7, GM-CSF; Chemokine, for example eotaxin; Collagen; Osteocalcin; The glutinous albumen etc. that connects of bone; Person of skill in the art will appreciate that this point.
In another embodiment, the present invention's composition of being used for the treatment of osteopathy can comprise one or more compounds as herein described, one or more extra bones promote property compound and osteogenic cells.In one embodiment, osteogenic cell can be to be induced to differentiate into osteoblastic stem cell or progenitor cell.In another embodiment, described cell can be a scleroblast.In another embodiment, can be to the nucleic acid of individual administration coding bone promotion property compound, this should be considered to part of the present invention.
In one embodiment, method of the present invention comprise contain be administered for the treatment osteoporosis compound.In another embodiment, method of the present invention comprises to drug compound (with the SERM associating), is used for the treatment of osteoporosis.In another embodiment, described SERM is a tamoxifen, 4-hydroxyl tamoxifen, idoxifene, toremifene, Ao Peimifen, bend Lip river former times phenol, Reynolds former times sweet smell, arzoxifene, WAY 140424, PPT (1,3,5-three (4-hydroxy phenyl)-4-propyl group-1H-pyrazoles), DPN (diaryl propionitrile), Lasofoxifene, piperazine spray former times sweet smell, EM-800, EM-652, nafoxidine, zindoxifene, Tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780, Clomiphene, MER-25, diethylstilbestrol, coumestrol, genistein, GW5638, LY353581, zuclomifene, Enclomifene, delmadinone acetate, DPPE, (N, N-diethyl-2-{4-(phenyl methyl)-phenoxy group } ethamine), TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, Pu Linbeirui, ERB-041, WAY-397, WAY-244ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, [18F] FEDNP, LSN-500307, AA-102, Herba Scutellariae Barbatae, CT-101, CT-102, VG-101.
In another embodiment, method of the present invention comprises with the described SARM compound of diphosphonate Combined Preparation and is used for the treatment of osteoporosis that described diphosphonate is Ah 's phosphonate for example, tiludronic acid (tiludroate), sodium clodronate (clodroniate), pamidronate disodium, hydroxyl ethyl phosphine hydrochlorate, Ah 's phosphonate, azoles is bent phosphonate (zolendronate), ineadronic acid disodium (cimadronate), neridronic acid sodium (neridronate), minodronic acid (minodronic acid), according to class's phosphonate, risedronate or homoresidronate.
In another embodiment, method of the present invention comprises that for example salmone (salmon), Turbocalcin, SUN-8577 or the described compound of TJN-135 Combined Preparation are used for the treatment of osteoporosis with thyrocalcitonin.
In another embodiment, the method for treatment osteoporosis of the present invention comprises the described SARM compound of the following material administration of associating: a) vitamins D or derivative, for example ZK-156979; B) Vitamin D Receptor part and analogue, for example calcitriol, calcitriol (topitriol), ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 or DP-035; C) oestrogenic hormon, oestrogen derivatives or premarin; D) antiestrogen, progestogen or synthetic estrogen/progestogen; E) RANK part monoclonal antibody, for example denosumab (being called AMG162 (Amgen) in the past); F) α ν β 3 integrin receptor antagonistses; G) osteoclast cavity type atpase inhibitor; H) in conjunction with the osteoclast receptor antagonist of VEGF; I) Calcilytic; J) PTh (parathyroid hormone) and analogue, PTHrP analogue (parathyroid hormone-related peptide); K) cathepsin K inhibitor (AAE581 etc.); L) Strontium Ranelate; M) tibolone; N) HCT-1026, PSK3471; O) maltose gallium (gallium maltolate); P) Nutropin AQ; Q) prostaglandin(PG) (being used for bone); R) p38 kinases inhibitor; S) bone morphogenetic protein; T) BMP antagonism inhibitor; U) HMG-CoA reductase inhibitor; V) vitamin K or derivative; W) according to general brass; X) fluoride salt; Y dietary calcium supplement and z) osteoprotegerin.
In one embodiment, method of the present invention is used for the treatment of by hormone disturbance, destruction or uneven disease that cause or associated or illness.In one embodiment, described hormone disturbance, destruction or imbalance comprise that hormone is excessive.In another embodiment, described hormone disturbance, destruction or imbalance comprise hormonoprivia.In one embodiment, described hormone is a steroid hormone.In another embodiment, described hormone is an oestrogenic hormon.In another embodiment, described hormone is a male sex hormone.In another embodiment, described hormone is a glucocorticosteroid.In another embodiment, described hormone is a reflunomide.In another embodiment, described hormone is lutropin (LH).In another embodiment, described hormone is follicle stimulating hormone (FSH).In another embodiment, described hormone is any other hormone known in the art.In another embodiment, described hormone disturbance, destruction or uneven relevant with menopause.In another embodiment, described hormone disturbance, destruction or imbalance and male climacteric, vasomotion male climacteric syndrome, mammogenesis male climacteric, muscle strength and/or function reduction, bone strength and/or function reduction and angry relevant.In another embodiment, hormonoprivia is the result of particular procedure, as treats the by product of individual disease or illness.For example, described hormonoprivia can be the result as the male sex hormone consumption of individual prostate cancer therapy.Every kind of possibility representative independently embodiment of the present invention.
In another embodiment, the present invention relates to treat Sarcopenia or emaciation and relative illness (for example osteopathia or illness).
In one embodiment, the invention provides the following purposes of compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination: 1) treatment muscular atrophy; 2) prevention muscular atrophy; 3) muscle loss that treatment, prevention, compacting, inhibition or minimizing cause owing to muscular atrophy; 4) treatment, prevention, inhibition, minimizing or compacting are owing to the myatrophy of muscular atrophy; And/or 5) treatment, prevention, inhibition, minimizing or compacting are owing to the mytolin katabolism of muscular atrophy; And/or treatment, prevention, inhibition, minimizing or compacting are owing to the myatrophy of end-stage renal disease or CKD; And/or 6) treatment, prevention, inhibition, minimizing or compacting are fragile.
In another embodiment, the purposes that is used for the treatment of the compound of the individuality of suffering from muscular atrophy or any illness as herein described comprises that administration comprises the pharmaceutical composition of compound as herein described.In another embodiment, described dosing step comprises and gives described individuality with the described pharmaceutical composition of liquid form through intravenously, intra-arterial or intramuscularly; Subcutaneous heeling-in contains the piller of described pharmaceutical composition in described individual body; Oral described pharmaceutical composition to described individual administration liquid or solid form; Or to the described pharmaceutical composition of skin surface topical application of described individuality.
Muscle is the bodily tissue that mainly is used as propulsion source.The muscle of health has three types: a) skeletal muscle---be responsible for the four limbs of health and the muscle of external region motion; B) cardiac muscle---cardiac muscle; And c) unstriated muscle---be arranged in the muscle of artery and intestines wall.
In this article, expendable (wasting) illness or obstacle definition are for being the illness or the obstacle of feature with unusual the carrying out property loss of body weight, organ quality or liver mass at least in part.The expendable illness can be used as disease for example cancer or infection the result and take place, or be attributable to physiology or metabolism state, for example because of CBR or when limbs are fixed (for example in casting mold), take place uselessly use sexual maladjustment.The expendable illness also can be that the age is relevant.The feature of losing weight that takes place in the expendable disease processes can be the minimizing of TBW or organ weight's minimizing, for example owing to the bone amount of tissue protein minimizing or the minimizing of muscle mass.
In one embodiment, be used alternatingly as this paper, " myatrophy (muscle wasting) " or " myatrophy (muscular wasting) " refers to the carrying out property loss of muscle mass and/or the decay of carrying out property and the degeneration of muscle, comprises the skeletal muscle of controls movement or the cardiac muscle and the unstriated muscle of voluntary muscle and control heart.In one embodiment, described myatrophy illness or obstacle are chronic myatrophy illness or obstacle." chronic myatrophy " is defined as the chronic progressive external decay of chronic (promptly continue a very long time) the carrying out property loss of muscle mass and/or muscle in this article and degenerates.
The muscle mass loss that takes place in the myatrophy process can be with the mytolin decomposition that causes owing to mytolin katabolism or be degraded to feature.Protein catabolism takes place because of the protein synthesis of unusual high speed protein degradation, unusual low speed or this combination of two kinds.Be the mytolin katabolism that causes of protein degradation or low protein synthesis by height or consume the minimizing and the myatrophy that all can cause muscle mass.Term " katabolism " has the implication of generally knowing in this area, is meant the metabolism of energy burning form especially.
Myatrophy can be used as the result of symptom, disease, illness or obstacle and takes place.In one embodiment, described symptom, illness, disease or illness are chronic.In another embodiment, described symptom, illness, disease or illness are genetic.In another embodiment, described symptom, illness, disease or illness are neural.In another embodiment, described symptom, illness, disease or illness are infective.As described herein, symptom, disease, illness or the obstacle of administration compound of the present invention and composition are the consumption (i.e. loss) that directly or indirectly produces muscle mass, the i.e. disease of muscular atrophy for it.
In one embodiment, Ge Ti myatrophy is caused by muscular dystrophy, myatrophy, the X spinobulbar muscular atrophy (SBMA) of described individuality.
Described muscular dystrophy is a heredopathia, it is characterized in that the decay of carrying out property and the degeneration of the skeletal muscle or the voluntary muscle of controls movement.Cardiac muscle and some other involuntary muscles also are subjected to the influence of the muscular dystrophy of some form.The principal mode of muscular dystrophy (MD) is: Di Xienei muscular dystrophy, myotonic dystrophy, Di Xienei muscular dystrophy, Duchenne muscular dystrophy, limb muscular dystrophy, face omoplate arm muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy and EDMD.
Muscular dystrophy can influence the crowd of institute's has age.Although some form at first occurs in baby or children, other may be up to middle age or more late just appearance.Di Xienei MD is prevailing form, generally influences children.Myotonic dystrophy is the most common disease in the adult in these diseases.
Myatrophy (MA) is with the feature that is reduced to of the consumption of muscle or minimizing and muscle mass.For example, poliomyelitis later stage MA is as the part of poliomyelitis poliomyelitis later stage syndrome (PPS) and the amyotrophy that takes place.Described atrophy comprises weakness, muscular fatigue and pain.
The MA of other type is X spinobulbar muscular atrophy (SBMA is also referred to as the Kennedy disease).This disease is caused by the defective of the androgen receptor gene on the X chromosome, only influences the male sex, and it showed effect in the Adulthood.Because main diseases is because of being the androgen receptor sudden change, so androgen replacement is not the popular therapeutic strategy.Some investigation are arranged, wherein give exogenous testosterone propionate to improve androgenic level, this is hopeful to overcome androgen insensitivity and the anabolism effect may be provided.Yet, use the testosterone of excusing from death reason level to be used for additional limitation and other potential severe complication of having.
Sarcopenia is the debilitating disease that torments old man and chronic, it is characterized in that the loss of muscle mass and function.And the increase of lean mass reduces relevant with the M ﹠ M of some muscular atrophy.And other situation and illness also are related with muscular atrophy and can be caused myatrophy.For example, studies show that, in the serious case of chronic low back pain, the paraspinal muscle atrophy occurs.
Myatrophy consumes also relevant with advanced age with other tissue.Believe that in the elderly, asthenia universalis is owing to myatrophy.Along with wearing out of health, the skeletal muscle of more ratios is replaced by fibrous tissue.As a result, muscle power, performance and endurance significantly descend.
Because i or I and be in hospital for a long time or for example when limbs are fixed, take place uselessly also can cause amyotrophy or the consumption of other tissue with sexual maladjustment.Studies show that, in the patient who suffers from damage, chronic disease, burn, wound or cancer who is in hospital for a long time, long-term one-sided myatrophy occurs and lose weight.
Central nervous system (CNS) damage or infringement are also relevant with other expendable illness with amyotrophy.CNS damage or infringement can be caused by for example disease, wound or pharmaceutical chemicals.Its example has central nervous system injury or infringement, peripheral nerve injury or infringement and Spinal injury or infringement.In one embodiment, CNS infringement or damage comprise Alzheimer (AD), angry (mood), apositia, anorexia nervosa, apositia and/or the confidence (mood) relevant with aging.
In another embodiment, myatrophy and the consumption of other tissue may be caused that can treat with compound of the present invention and composition, this represents their embodiment by alcoholism.
In one embodiment, the invention provides the purposes that compound as herein described or its analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination are used for the treatment of individual wasting diseases, obstacle or illness.
In one embodiment, described wasting diseases of being treated, obstacle or illness are relevant with chronic disease.
In some embodiments, any expendable illness that the present invention relates to treat may be in myatrophy, lose weight, show in malnutritive, the hunger or any function consumption or disappearance that reduces owing to tissue mass.
In some embodiments, wasting diseases or illness, for example emaciation, malnutrition, tuberculosis, leprosy, diabetes, nephropathy, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, Sarcopenia, pulmonary emphysema, osteomalacia or myocardosis, can be by method of the present invention, through administration SARM compound as herein described, comprise it composition, additionally or additional treat for the illness of being treated provides medicine, compound or the medicament of curative effect.
In some embodiments, consumption is owing to infect enterovirus, Epstein-Barr virus, zoster, HIV, trypanosome, influenza (influenze), Coxsackie virus, Rickettsiae, Trichinella spiralis, schistosomicide or mycobacterium, in some embodiments, the invention provides its methods of treatment.
Emaciation be cause by disease or as the weakness of disease side reaction with lose weight.Cardiogenic emaciation, promptly the mytolin consumption of cardiac muscle and skeletal muscle is the feature of congestive heart failure.Cancer cachexia is the syndrome that occurs in the patient who suffers from solid tumor and malignant hematologic disease, and it shows as losing weight that mass consumption because of fatty tissue and thin muscle mass causes.
Emaciation also sees acquired immune deficiency syndrome (AIDS) (AIDS), and the relevant myopathy of human immunodeficiency virus (HIV) and/or myasthenia/myatrophy are the relatively more logical clinical manifestations that becomes of AIDS.Suffer from the relevant myopathy of HIV or myasthenia/amyotrophic individuality and stand myasthenia serious weight loss, whole body or near-end, tenderness and myatrophy usually.
In some embodiments, the invention provides to be used for the treatment of and individual infect, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises the composition immunomodulator to individual administration inclusion compound and immunomodulator, anti-infection agent, gene therapeutic agents or their combination.In one embodiment, described anti-infection agent can be anti-mycotic agent, antibacterial agent, antiviral agent or antiparasitic or their combination.In some embodiments, infection comprises actinomycosis, anaplasmosis, anthrax, aspergillosis, microbemia, the bacterium mycosis, Bartonella infects, sausage poisoning, brucellosis, the Bai Huoerde coli infections, Campylobacter infects, moniliosis, cat scratch disease, chlamydozoan infects, cholera, clostridium infects, coccidioidomycosis, cross infection, torulosis, tinea, the diphtheria disease, Ehrlichiosis, coli-infection, necrotizing fasciitis, fusobacterium infects, gas gangrene, gram-negative bacterial infections, gram positive bacterial infection, histoplasmosis, pustulosis, klebsiella infects, legionellosis, leprosy, leptospirosis, the Li Site bacterium infects, Lyme disease, Madurella, pseudoglanders, mycobacterial infections, mycoplasma infection, mycosis, the Nuo Kaer bacterium infects, onychomycosis, pestilence, pneumococcal infection, pseudomonas infection, psittacosis, Q heat, rat-bite fever, typhinia, rheumatic fever, rickettsial infection, Lip river Ji Shan spot heat, Salmonella infection, scarlet fever, the scrub typhus typhus fever, septicemia, sexually transmitted disease (STD), staphylococcal infections, streptococcal infection, tetanus, tick transmissible disease (tick-borne diseases), tuberculosis, tularaemia, typhoid fever, LBT, vibrio infection, yaws, Yersinia infects, the zoonosis, zygomycosis, acquired immune deficiency syndrome (AIDS), Adenoviridae infects, Alphavirus infects, arboviruses infects, the Borna disease, bunyaviridae infects, embedding cup Viraceae infects, varicella, coronaviridae infects, Coxsackie virus infection, cytomegalovirus infection, singapore hemorrhagic fever, dna virus infection, the contagion variola, encephalitis, arboviruses, the Epstein-barr virus infection, erythema infectiosum, Hantaan virus infects, hemorrhagic fever, viral hepatitis, viral human herpes simplex, zoster, herpes auris, herpetoviridae infects, infectious monocytosis, people's lassa fever, measles, molluscum contagiosum, mumps, Paramyxoviridae infects, sandfly fever, polyomavirus infects, rabies, respiratory syncytial virus infects, Rift Valley fever, picornavirus infection, rubella, slow virus infection, smallpox, subacute sclerosing panencephalitis, tumour virus infects, wart, west Nile fever, virus disease, yellow jack, loeschiasis, anisakiasis, ascariasis, babesiosis, the blastocystis hominis infects, bedbug bite, cestode infection, American trypanosomiasis, cryptosporidiosis, sporozoite infects ring, cysticercosis, the double-core loeschiasis, diphyllobothriasis, dracunculiasis, hydatidosis, ectoparasitic infection, filaricide, giardiasis, verminosis, hookworm infection, larva migrans, leishmaniasis, the lice parasitism, loaiasis, malaria, infect, myiosis, onchocerciasis, protozoan infection, scabies, schistosomicide, (parasitic) tetter, strongyloidiasis, teniasis, toxocariasis, toxoplasmosis, trichonematosis, trichomonacide, trypanosomiasis, tsetse fly disease or whipworm infection.
In some embodiments, the invention provides and be used for the treatment of individual flesh osteopathia, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment central nervous system, treatment metabolic disease, medicine, gene therapeutic agents, the medicine of treatment endocrine system or their combination of treatment wasting diseases.In some embodiments, the flesh osteopathia comprises fetal rickets, acquired hyperostosis syndrome, acrocephalosyndactylia (toe) deformity, sacroiliitis, articular contracture, joint disease, the neurogenicity bursitis, cartilage disease, cleidocranial dysplasia, reel foot, fascial compartment syndrome, craniofacial dysostosis, craniosynostosis, dermatomyositis, dupuytren's contracture, nanism, Ellis-van Creveld syndrome, chondrodysplasia, acid cytosis muscle pain syndrome, exostosis, fascitis, fatigue syndrome, fibromyalgia, fibrous dysplasia of bone, polyostotic fibrous dysplasia, splayfoot, foot deformity, freiberg's disease, chonechondrosteron, Goldenhar syndrome, gout, intoe, hip dislocation, hyperostosis, intervertebral disk displacement, kabuki's syndrome (kabuki make-up syndrome) of making up, cervical vertebrae synostosis, Lan-Ji syndrome, legg-Perthes disease, sway back, mandibulofacial dysostosis, limb bone line shape hypertrophy, mitochondrial myopathy, muscular cramp, muscular spasticity, muscular dystrophy, the muscle skeleton deformity, the flesh osteopathia, myositis, myositis ossificans, myotubular myopathy, osteitis deformans, osteoarthritis, osteochondritis, osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteopetrosis, osteoporosis, Poland syndrome, relapsing polychondritis, polymyalgia rheumatica, polymyositis, rhabdomyolysis, rheumatism, russell-Silver syndrome, scheuermann's disease, scoliosis, seper's disease/calcaneal apophysitis, spinal disease, the spinal cord osteophytosis, spinal canal stenosis, ankylosing spondylitis, spondylolisthesis, sprengel's deformity, synovitis, the tendon pathology, tennis elbow, tenosynovitis, lethality underdevelopment or Tietze syndrome.
In some embodiments, the invention provides and be used for the treatment of individual digestive system, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, medicine, VITAMIN or their combination of the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment central nervous system, treatment gastro-intestinal system, anti-infective, treatment metabolic disease, gene therapeutic agents, treatment endocrine system.In some embodiments, gastrointestinal illness comprises adenomatous polyposis coli, Alagille syndrome, Anus Diseases, ecphyaditis, Barrett esophagus, Biliary atresia, biliary tract, caroli disease, celiac disease, cholangitis, cholecystitis, cholelithiasis, ulcerative colitis, Crohn's disease, dysphgia, duodenal ulcer, dysentery, pseudomembranous enterocolitis, oesophagus loses relaxation disease, atretolemia, esophagitis, exocrine pancreatic function is incomplete, fatty liver, scoracratia, gastritis, hypertrophic gastritis, gastro-enteritis, gastroesophageal reflux, stomach flesh paresis, hemorrhoid, hepatic vein thrombosis forms, hepatitis, chronic hepatitis, diaphragmatocele, hiatal hernia, Hirschsprung disease, hypertension (HTN), portal hypertension, inflammatory bowel disease, intestinal disease, intestinal tumor, enteric nervous unit heteroplasia, intestinal obstruction, irritable bowel syndrome, lactose intolerance, liver cirrhosis, hepatopathy, Meckel's diverticulum, pancreatic disease, pancreatic neoplasm, pancreatitis, peptide ulceration, jeghers' syndrome, rectitis, recial disease, proctoptosis, short bowel syndrome, tracheo esophageal fistula, Whipple disease or Zollinger Ellison syndrome.
In some embodiments, the invention provides and be used for the treatment of individual mouthful of jaw disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the present invention includes to individual administration composition the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, anti-infective, treatment wasting diseases, gene therapeutic agents, treatment endocrine system, VITAMIN or their combination.In some embodiments, a mouthful jaw disease comprises that tongue frenulum is too short, bruxism, mouth are burnt syndrome, cheilitis, cherubism, harelip, dentigerous cyst, oulitis, benign migratory glossitis, herpes labialis, Ludwig's angina, macroglossia, Mai-Luo two Cotards, periodontal disease, Pi Aier robin syndrome, mandibular protrusion, salivary gland disease, hydrostomia, aphthous stomatitis, temporomandibular joint (TMJ) obstacle, temporomandibular joint disturbance syndrome or xerostomia.
In some embodiments, the invention provides and be used for the treatment of individual respiratory tract disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, medicine, VITAMIN or their combination of the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment central nervous system, treatment cardiovascular systems, anti-infective, treatment wasting diseases, gene therapeutic agents, treatment endocrine system.In some embodiments, respiratory tract disease comprises obstruction of the air passage, breathlessness, asbestosis, asthma, asthma inductive myasthenia or bone weakness, atelectasis, berylliosis, disease of bronchus, bronchiectasis, bronchiolitis, the bronchiolitis obliterans organized pneumonia, bronchitis, broncho-pulmonary dysplasia, chronic obstructive pulmonary disease (COPD), flu, cough, the thoracic cavity empyema, epiglottitis, myopathy or osteopenia that glucocorticosteroid (GC) causes, spitting of blood, pulmonary hypertension, hyperventilation, Kartagener syndrome, pulmonary abscess, tuberculosis, MAS, hydrothorax, pleuritis, pneumonia, pneumothorax, alveolar protein hemachromatosis, chronic obstructive pulmonary disease, pulmonary edema, pulmonary infarction, pulmonary emphysema, pulmonary fibrosis, respiratory distress syndrome, the newborn respiration allergy, respiratory tract infection, rhinoscleroma, scimitar syndrome, the serious acute respiratory organ is comprehensively sick, silicosis, sleep apnea, central authorities stridulate, tracheostenosis, muscle mass or bone amount owing to asthma reduce, consumption in the chronic obstructive pulmonary disease (COPD), Wei Genashi granuloma or Whooping cough.
In some embodiments, the invention provides and be used for the treatment of individual otolaryngologic disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, anti-infective, treatment wasting diseases, gene therapeutic agents, treatment endocrine system, VITAMIN or their combination.In some embodiments, otolaryngologic disease comprises cholesteatoma of middle ear, croup, deafness, nasal bleeding, hearing loss, hyperacusis, labyrinthitis, laryngitis, laryngomalacia, laryngostenosis, mastoiditis, Meniere, nasal obstruction, nasal polyp, otitis, otorhinolaryngology disease, otosclerosis, pharyngitis, presbyacusis, retropharyngeal abscess, rhinitis, sinusitis paranasal sinusitis, tinnitus, tonsillitis, the perforation of ear drum, vestibular neuronitis, paralysis vocal cord or voice disorder.
In some embodiments, the invention provides and be used for the treatment of individual nervous system disorders, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, medicine, VITAMIN or their combination of the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, treatment central nervous system, anti-infective, treatment metabolic disease, treatment wasting diseases, gene therapeutic agents, treatment endocrine system.In some embodiments, nervous system disorders comprises autonomic nervous system diseases, central nervous system disease, cranial nerve disease, demyelination, nervous system malformation, neurological performance or neuromuscular disease.
In some embodiments, autonomic nervous system diseases comprises causalgia or reflectivity sympathetic nerve malnutrition.
In some embodiments, central nervous system disease comprises Alzheimer, arachnoiditis, cerebral abscess, cerebral ischemia, central nervous system infection, cerebral palsy, cerebrovascular disorder, corticobasal degeneration (corticobasal ganglionic degeneration, CBGD), Creutzfeldt-Jakob syndrome, dandy-Walker syndrome, dull-witted, encephalitis, encephalomyelitis, epilepsy, epilepsy inductive hypogonadism and/or hypermetabolism state, essential tremor, Friedreich ataxia, Jie Ciman-Si Tuosile-Shi Yin restrains sick, hallerman-Streiff syndrome, Huntington Chorea, hydrocephalus, anoxic, insomnia, cerebral ischemia attack (ischemic attack), Kuru disease, Landau-Kleffner syndrome, Lewy body disease, Ma-Yue disease, Meige syndrome, meningitis, bacterial meningitis, viral meningitis, migraine, dyskinesia, multiple system atrophy, myelitis, olivopontocerebellar atrophy, Parkinson's disease, Parkinson's obstacle, poliomyelitis, post poliomyelitis syndrome, prion disease, pseudotumor cerebri, orthostatic hypotension syndrome, infantile convulsion, diseases of spinal cord, supranuclear paralysis, syringomyelia, the thalamus disease, the convulsive dyskinesia, many moving tourette syndromes or uveomeningoencephalitis syndrome.In some embodiments, described central nervous system disease is a cystic fibrosis inductive hypogonadism state.
In some embodiments, the cranial nerve disease comprises neuritis facial, cranial nerve disease, facial semiatrophy, face ache, glossopharyngeal nerve disease, Moebius syndrome or trigeminal neuralgia.
In some embodiments, central nervous system disease comprises damage or the infringement to central nervous system (CNS).In some embodiments, may be relevant to damage or the infringement of CNS with muscular atrophy.Damage or infringement to CNS can be caused by for example disease, wound or chemical reagent.Its example is central nervous system injury or infringement, peripheral nerve injury or infringement and Spinal injury or infringement.
The research that relates to Spinal injury (SCI) patient shows that behind SCI, central neurotransmitter may change, and causes the hypothalmus-pituitary-adrenal axis dysfunction, and its destruction causes the serious decline of testosterone and other hormonal readiness.SCI or other acute illness or wound characteristic ground comprise that katabolism strengthens and the anabolism activity is lowered, and cause being easy to lose the illness of weight reducing body tissue, and often follow disorderly nutritional utilization.The influence of the loss of lean mass comprises wound expansion and healing mechanism of damaged, makes problem further complicated.Because it is fixing that malnutritive and proteolysis metabolism adds, the patient of Spinal injury is in the risk of trouble bedsore highly.
In one embodiment, method of the present invention can be treated various CNS damages.In one embodiment, the CNS damage can refer to the decomposition of neuron membrane, perhaps in another embodiment, refers to that nerve can not produce or propagate nerve impulse, perhaps in another embodiment, refers to the death of neurocyte.Damage comprises the infringement of the normal merit function of the direct or indirect CNS of influence.Described damage may be structural, physical property or mechanical injuries, and may be under the situation of extruding, compression or stretching nerve fiber be impacted by health and cause.Perhaps, described cytolemma may be because of imbalance of disease, chemical combination or physiological function obstacle, for example anoxic (for example palsy), aneurysma or perfusion and destroyed or degraded again.The CNS damage comprises without limitation for example to retinal ganglial cells infringement, traumatic brain injury, the damage that palsy is relevant, damage, Spinal injury (comprising monoplegia, diplegia, paraplegia, hemiplegia and tetraplegia), neural proliferative disorders or the neuropathic pain syndrome that cerebral aneurysm is relevant.
Since to the damage of Mammals spinal cord, the connection fracture in the spinal cord between the nerve.This damage blocking-up is subjected to the flowing of nerve impulse of the nerve tract of this damage influence, and the result damages sensory function and motor function.Damage to spinal cord may be because of compression or other contusion, spinal cord extruding or the cut-out of spinal cord.Spinal cord cuts off (being also referred to as " crosscut " herein), and the cut-out fully that may be spinal cord maybe may be an incomplete cut-off.
In some embodiments, the treatment method of suffering from the individuality of CNS damage (or in another embodiment for suffering from Spinal injury) may be followed with the electricity irritation of damage location and administration purine nucleoside or its analogue (for example described in the U.S. Patent Application Publication 20040214790A1) and treat described individuality.
In some embodiments, demyelination comprises adrenoleukodystrophy, Alexander disease, canavan's disease, demyelinating disease, Schilder diffuse cerebrosclerosis, globoid cell leukodystropy, metachromatic leukodystrophy, multiple sclerosis or optic neuromyelitis.
In some embodiments, nervous system malformation comprises A-Cai Er Shi deformity, charcot-Marie-Tooth disease, brain bulging, heredity motion and esthesionosis, septum pellucidum-hypoplasia of optic nerve, hemirachischisis or spinal dysraphism.
In some embodiments, the neurological performance comprises agnosia, amnesia, anomia, aphasia, apraxia, backache, Brown-Se﹠1﹠quard syndrome, cerebellar ataxia, chorea, communication disorder, confusion of consciousness, dizzy, dislexia, dystonia, facioplegia, facsiculation, gait disorder, nervous headache, hemiplegia, dysmnesia, mental retardation, mutism, myoclonus, cervicodynia, the non-verbal learning obstacle, olfactory disorder, pain, paralysis, phantom limb, prosopagnosia, tetraplegia, epileptic seizures, convulsion is twin, speech disorder, the synaesthesia tardive dyskinesia, dysgeusia, torticollis, tremble, teeth clenched, the loss of consciousness or dizzy.
In some embodiments, neuromuscular disease comprises amyotrophic lateral sclerosis, brachial plexus neuritis, brachial plexus neuropathy, bulbar paralysis, carpal tunnel syndrome, cubital tunnel syndrome, diabetic neuropathy, dysautonomia, guillain-Barre syndrome, heredity sensation and autonomic nervous system neuropathy, the Miller fisher's syndrome, motor neuron, Duchenne-Arandisease, myasthenia gravis, congenital structural myopathy, neural entrapment syndrome, neurodynia, neuromuscular disease, familial periodic paralysis, peripheral nervous disease, POEMS syndrome, polyneuropathy, polyradiculopathy, refsum, sciatica, children's Duchenne-Arandisease, stiff man syndrome (stiff-person syndrome), syndrome of chest outlet or ulnar nerve compression syndrome.
In one embodiment, the method that the individuality of nervous system disorders is suffered from treatment comprises any Secondary cases illness for the treatment of described individuality, and described illness suffers from nervous system disorders by described individuality and causes that wherein some have narration in this article.
In some embodiments, the invention provides and be used for the treatment of individual disease of eye, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, treatment cardiovascular systems, anti-infective, treatment wasting diseases, gene therapeutic agents, treatment endocrine system, VITAMIN or their combination.In some embodiments, disease of eye comprises the invisible outer retina pathology of acute regionality (acute zonal occult outerretinopathy), Adie syndrome, albinism, eyes amaurosis (ocular-amaurosis), amblyopia (fugax), amblyopia (amblyopia), irideremia, anisocoria, anophthalmia, aphakia, astigmatism, marginal blepharitis, blepharoptosis, winking spasm, blind, cataract, chalazion, choroidoretinitis, choroideremia, eye is damaged, color defect, conjunctivitis, keratopathy, cerneal dystrophy, corneal edema, keratohelcosis, diabetic retinopathy, diplopia, distichia, dry eye syndrome, the Duane duane syndrome, ectropion, trichoma, esotropia, the iris pigment exofoliation syndrome, external strabismus, ophthalmorrhagia, the eyes knurl, eyelid disease, suspended substance, extensive fibrosis syndrome (general fibrosis syndrome), glaucoma, the ring-type atrophy, hemianopsia, hermanski-Pudlak syndrome, sty, Horner syndrome, long sight, hyphema, iritis, Kearns-Sayer syndrome, keratitis, keratoconus, lacrimal apparatus disease, lacrimal duct abstruction, the crystal disease, macular degeneration, ommatidium, myopia, pathological nystagmus, Kearns-Sayer, oculomotor nerve disease, ophthalmoplegia, optic atrophy, optic nerve disease, optic neuritis, optic neuropathy, orbital cellulitis, papilloedema, Peter is unusual, presbyopia, pteryium, the pupil imbalance, ametropia, retinal detachment, retinal diseases, retinal vein occlusion, retinitis pigmentosa, retinopathy of prematurity, retinoschisis, scleritis, dim spot, stravismus, the Thygeson superficial punctate keratitis, trachoma, uveitis, white point syndrome, visual disorder or disorder of vitreous body.
In some embodiments, the invention provides treatment individual urinary tract and/or male genital disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, medicine, VITAMIN or their combination of the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment gastro-intestinal system, anti-infective, treatment kidney, treatment metabolic disease, the medicine of treatment wasting diseases, gene therapeutic agents, treatment endocrine system.In some embodiments, urologic disease and/or male genital disease comprise the anti-GBM disease; balanitis; ectopia vesicae; tumor of bladder; cryptorchidism; interstitial cystitis; nephrogenic diabetes insipidus; epididymitis; Fournier gangrene; glomerulonephritis; Goodpasture; hemospermia; blood urine; hemolytic uremic syndrome; nephrohydrosis; hypospadia; impotence; sterile; urinary stone disease; acute renal failure; chronic renal failure; acute tubular necrosis; sponge kidney; the polycystic Kidney dysplasia; hereditary nephritis; ephrosis; nephrotic syndrome; enuresis nocturna; oliguresis; penile disease; penile induration; tumor of penis; phimosis; priapism; prostatosis; benign prostatic hyperplasia; tumor of prostate; proteinuria; pyelonephritis; reiter disease; the Renal artery blocks; torsion of spermatic cord; testis disease; urethrostenosis; urethritis; uroschesis; urinary tract infection; dysuria; urinary tract and male genital disease; urologic disease; varicocele; bladder or urethra reflux.
In some embodiments, the invention provides the individual skin disorder of treatment, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the present invention comprises and gives the group of individuals compound, the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, treatment skin disorder, anti-infective, gene therapeutic agents, treatment endocrine system, VITAMIN or their combination.In some embodiments, skin disorder comprises acne, actinic keratosis, alopecia, androgenetic alopecia, alopecia areata, the chemotherapeutic alopecia of secondary, the radiotherapeutic alopecia of secondary, by the alopecia of cicatrization inductive, the alopecia of stress-induced, vascular tumor, tinea pedis, aquagenic pruritus, atopic dermatitis, alopecia, premature alopecia, the alopecia of man's property, androgenetic alopecia, rodent cancer, burn, bedsore, behcets disease, marginal blepharitis, furuncle, the Bowen disease, bullous pemphigoid, recurrent canker sores, carbuncle, organize the honeycomb inflammation, chloracne, the trick chronic dermatitis, dyshidrosis, cold sore, contact dermatitis, creeping eruption, dandruff, dermatitis, dermatitis herpetiformis, dermatofibroma, diaper rash, eczema, epidermolysis bullosa, erysipelas, erythroderma, the scratch bubble, Genital warts, suppurative hidradenitis, urticaria, hyperhidrosis, ichthyosis, pustulosis, marginality dermatophyte disease, Kaposi sarcoma, keloid, keratoacanthoma, keratosis pilaris, lice infects, lichen planus, chronic simple lichen, lipoma, poradenolymphitis, malignant melanoma, black spot, miliaria, molluscum contagiosum, nummular dermatitis, Paget's disease of the nipple, pediculosis, pemphigus, Perioral Dermatitis, photoallergy, photosensitization, pityriasis rosea, pityriasis rubra pilaris, psoriatic, raynaud's disease, tinea glabrosa (ring worm), rosacea, scabies, scleroderma, sebaceous cyst, seborrheic keratosis disease, seborrheic dermatitis, zoster, skin carcinoma, skin is superfluous, spider veins, squamous cell carcinoma, stasis dermatitis, tick is bitten, barber's itch, favus of the scalp, ringworm of the body, jock itch, the ringworm of the foot, onychomycosis, tinea versicolor, tinea, dermatophiliasis, purplish or white patches on the skin wind disease or wart.
In one embodiment, described skin disorder is wound or burn.In some embodiments, find that wound and/or ulcer are outstanding or on mucomembranous surface or the result of organ infarction from skin.Wound may be the result of soft tissue defects or infringement or potential disease.In one embodiment, term " wound " refers to have the destructive somatic damage of normal weave construction integrity.This term also comprises term " sore ", " infringement ", " necrosis " and " ulcer ".In one embodiment, term " sore " refers to any infringement of skin or mucous membrane, and term " ulcer " refers to the SOL or the pouch on organ or tissue surface, its by the corruption of necrotic tissue from generation.Infringement is general with tissue defect is relevant arbitrarily.Downright bad relevant with the thanatogenic tissue that causes by infection, damage, inflammation or infarction.All these is comprised by term " wound ", described " wound " refers to any wound in any specific stage in the agglutination, the described stage comprises the stage before any healing begins, or even is producing specific wound (as surgical incision) (prophylactic treatment) stage before.
The example for the treatment of the wound that prevents and/or treats according to the present invention is, for example aseptic wound, contusion, cut wound, lacerated wound, non perforating wound (not having wherein promptly that skin destroys but the wound of structure below the damage), open wound, penetrating wound, perforating wound, stab, septic wound, subcutaneous wound etc.The example of sore has bedsore, aphtha, chrome ulcer, cold sore, pressurized ulcer etc.The example of ulcer is peptide ulceration, duodenal ulcer, stomach ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, Malabar ulcer, venereal ulcer (for example being caused by gonorrhoea (comprising urethritis, endocervicitis and rectitis)).Relevant with wound or sore can successful illness for the treatment of be burn, anthrax, tetanus, gas gangrene, scarlet fever (scalatina), erysipelas, Sycosis vulgaris, folliculitis, infectivity purulence born of the same parents' disease or epidermolysis purulence born of the same parents disease etc. according to the present invention.The use of term " wound " and " ulcer " and " wound " and " sore " often has certain overlapping, and these terms usually use at random.Therefore, as mentioned above, in this article, term " wound " comprises term " ulcer ", " infringement ", " sore " and " infarction ", and these terms do not use with making any distinction between, unless otherwise noted.
The wound kind for the treatment of according to the present invention treatment also comprises: i) general wound, for example surgical wound, wound, infectious wound, ischemia wound, scald wound, chemical wound, bleb wound; Ii) especially at the wound in oral cavity, for example exodontia back wound, particularly the dental pulp wound relevant with abscess, bacterium with the treatment tumour, viral or from immunogenicity ulcer and infringement, mechanical wound, chemical wound, scald wound, infected wound and lichen sample wound; Object lesson is bleb ulcer, herpetic stomatitis, acute necrosis noma and the mouth syndrome of burning; The iii) wound on the skin, for example early stage of pyogenic infection of skin, burn (for example chemical burn, scald), infringement (bacillary, viral, from immunity), bite and surgical incision.Other wound sorting technique is: i) owing to surgical incision, the slightly scratch and the little tissue loss of slightly biting, or ii) serious tissue loss.The classification of back comprises ischemic ulcer, pressurized ulcer, fistula, tears, seriously bites, thermal burn and hinder (in soft tissue and sclerous tissues) and infarction for the district.
In other aspects of the present invention, wound to be prevented and/or treated is selected from aseptic wound, infarction, contusion, cut wound, lacerated wound, non perforating wound, open wound, penetrating wound, perforating wound, stabs, septic wound and subcutaneous wound.
The important wound of other relevant with the present invention is as ischemic ulcer, pressurized ulcer, fistula, seriously bite, thermal burn and the wound of hindering for the district.
In one embodiment, compound as herein described is used for wound healing as the adjuvant of Physiotherapy/rehabilitation or as anabolica.In another embodiment, compound as herein described is used to promote the healing of anterior cruciate ligament (ACL) or inboard ligamentaum cruciatum (MCL) damage or quicken ACL or MCL operative results.In another embodiment, compound as herein described is used to improve motor capacity.In another embodiment, compound as herein described is used for the treatment of burn.In another embodiment, compound as herein described is used to promote regenerating bone or cartilage.In another embodiment, compound as herein described is used to prevent, treat or reverse and secular critical illness, pulmonary dysfunction, respirator dependence, aging, AIDS, wound, surgical operation, congestive heart failure, myocardosis, burn, cancer, katabolism that COPD is relevant.In another embodiment, compound as herein described is used to prevent or reverse the protein catabolism that is caused by wound.In another embodiment, compound as herein described is used as: the adjuvant of the cauterization therapy of a) using in surgical operation (cauterization therapy) (laser or radiation) is to promote wound healing, b) adjuvant of psychrotherapy is to promote wound healing, c) chemotherapeutic adjuvant is with the prevention side effect, for example alopecia, hypogonadism, myatrophy, osteopenia, osteoporosis, Sarcopenia, LDL, triglyceride level (TG) or total cholesterol increase, HDL reduces.In another embodiment, compound as herein described is used for chronic katabolism state (stupor, expendable illness, hunger, eating disorder); Concurrency fracture and muscle damage; The critical illness that wherein has tangible muscle or bone to consume; And/or connective tissue disease and illness.
Ischemic ulcer and pressure ulcer be heal usually extremely slow wound, especially in this case, improve and healing fast is very important to patient certainly.And when healing improved and takes place sooner, the related expense of patient that this wound is suffered from treatment significantly reduced.
Relevant for the generation that hinder in the district with for example sclerous tissues moves to health from a position of health another position (for example transplanting).By the wound ten minutes pain that this operation causes, therefore, it is very valuable to improve healing.
Term " skin " comprises the epidermal area of skin with very wide significance use, under the situation that skin damages more or less, also comprises the skin corium of skin.Except stratum corneum, the epidermal area of skin is outer (epithelium) layer, and darker skin connective tissue layer is called corium.
In some embodiments, burn is relevant with the testosterone levels reduction, and hypogonadism postpones relevant with wound healing.In one embodiment, method of the present invention provides treatment to suffer from the individuality of wound or burn.
In some embodiments, the invention provides the method that is used to promote anterior cruciate ligament (ACL) or inboard ligamentaum cruciatum (MCL) wound healing or quickens ACL or MCL operative results.
In some embodiments, the invention provides and be used for the treatment of individual endocrine disorder, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, medicine, VITAMIN or their combination of the medicine of the medicine of the medicine of the medicine of described composition inclusion compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular system drug, treatment gastro-intestinal system, the medicine of treatment skin disorder, treatment central nervous system, anti-infective, treatment liver, the medicine of treatment kidney, treatment metabolic disease, the medicine of treatment wasting diseases, gene therapeutic agents, treatment endocrine system.In some embodiments, endocrine disorder comprises acromegaly, Addison disease, adrenal gland diseases, adrenal,congenital hyperplasia, androgen-insensitivity syndrome, congenital hypothyroidism, hypercortisolism, diabetes insipidus, diabetes, type 1 diabetes, diabetes B, diabetic ketoacidosis, empty sella syndrome, the incretory gland tumour, endocrine system disease, gigantosoma, gonadal disorder, Graves disease, hermaphrodite, aldosteronism, hyperglycemic hyperosmolar nonketonic coma, hyperpituitarism, hyperprolactinemia, hyperthyroidism, hypogonadism, hypopituitarism, hypothyroidism, kallman syndrome, Nelson syndrome, disease of parathyroid glands, disease of pituitary gland, autoimmune polyendocrine disease, delayed puberty, precocious puberty, renal osteodystrophy, thyroid disease, thyroid hormone resistance syndrome, thyroid tumor, thyroid nodule, thyroiditis, autoimmune thyroiditis, subacute thyroiditis or Wolfram syndrome.
In one embodiment, " hypogonadism " be by the sexual gland functional activation unusual reduce cause or be the illness of feature with it, and with growth and sexual development delay.
In some embodiments, the invention provides and be used for the treatment of individual urogenital disease and/or fertilizability, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the present invention comprises and gives the group of individuals compound, and described composition comprises medicine, the gene therapeutic agents of compound of the present invention and anticarcinogen, immunomodulator, anti-infective, treatment kidney, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, urogenital disease and/or fertilizability disease comprise miscarriage, spontaneous pelvis adhesion, vulvovaginal candidiasis, postpartum depression, gestational diabetes, psychologic dyspareunia, difficult labour, eclampsia, endometriosis, stillborn foetus, intrauterine growth retardation, rupture of fetal membranes is too early, female genital diseases, female genital organ tumor, hydatidiform mole, hyperemesis gravidarum, infertile, ovarian cysts, ovarian torsion, pelvic inflammatory disease, placenta disease, placental insufficiency, polycystic ovarian syndrome, polyhydramnios, postpartum hemorrhage, pregnancy complications, ectopic pregnancy, pruritus vulvue, puerperal, puerperal infection, salpingitis, trophoblastic tumor, cervical incompetence, inversion of uterus, uterine prolapse, vaginopathy, disease of vulva, vulva lichen sclerosus (vulvar lichen sclerosis).
In some embodiments, the invention provides and be used for the treatment of individual blood and/or lymphatic disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment metabolic disease of medicine, the treatment kidney of medicine, anti-infective, the treatment liver of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, blood and/or lymphatic disease comprise afibrinogenemia, anaemia, aplastic anemia, hemolytic anemia, congenital non-spherocytic anaemia (congenital nonspherocytic anemia), megaloblastic anemia, pernicious anemia, sicklemia, renal anemia, the angiolymphoid hyperplasia with eosinophilia, Antithrombin III lacks, Bernard-Soulier syndrome, blood coagulation disorder, blood platelet disorder, bean syndrome, cut eastern two Cotards, cryoglobulinemia, disseminated intravascular coagulation, the eosinophilia, the Erdheim-Chester disease, erythroblastic fetalis, Yi Wansi syndrome, factor V lacks, factor VII deficiency, factor X deficiency, factor XI deficiency, factor XII deficiency, Fanconi anemia, castleman disease, hemopathy, hemoglobinopathy, paroxysmal hemoglobinuria, hemophilia A, hemophilia B, hemorrhagic disease of newborn, histiocytosis, langerhans cell histiocytosis, non-langerhans cell histiocytosis, Job's syndrome, leukopenia, poradenolymphitis, LAM, lymphedema, methemoglobinemia, myelodysplastic syndrome, myelofibrosis, myeloid metaplasia, myeloproliferative diseases, neutropenia, paraproteinemia, the thrombocyte holding pond lack as, polycythemia vera, protein C lacks, protein s lacks, purpura, akembe, the thrombus thrombopenia, RH-isoimmunization, sarcoidosis, sarcoidosis, Sph, the lienal rupture, thalassemia, thrombocytasthenia, thrombopenia, Waldenstrom macroglobulinemia or von Willebrand disease.
In some embodiments, the invention provides and be used for the treatment of individual congenital, heredity or newborn child's illness, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment kidney of medicine, anti-infective, the treatment liver of medicine, the treatment central nervous system of medicine, the treatment skin disorder of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment medicine for cardiovascular system, treatment gastro-intestinal system, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, congenital, heredity or newborn child's illness comprise aicardi's syndrome, amniotic band syndrome, anencephalia, Angelman syndrome, ataxia telangiectasia, Bannayan-Zonana syndrome, Barth syndrome, basal cell naevus syndrome, beck-with-Wiedemann syndrome, Bloom syndrome, BOR, cat's eye syndrome, cerebral gigantism symphysic teratism syndrome (cerebral gigantism-charge syndrome), karyomit(e) 16 is unusual, karyomit(e) 18 is unusual, karyomit(e) 20 is unusual, chromosome 22 is unusual, Costello syndrome, cat's cry syndrome, Currarinosyndrome syndrome, cystic fibrosis, De Lange syndrome, 10q distally trisomy (distaltrisomy 10q), mongolism, ectodermal dysplasia, fetal alcohol syndrome, fetal disease, fetofetal transfusion, fragile X syndrome, cranio-carpo-tarsal dysplasia, abdomen splits, the congenital hereditary disease, umbilical hernia, holoprosencephaly, incontinentia pigmenti, ivemark's syndrome, jacobs' syndrome, jaundice, Klinefelter syndrome, larsen syndrome, laurence-Moon syndrome, agyria, microcephalus, the 9p monosomy, nail patella syndrome, neurofibromatosis, neurone ceroid lipofuscinosis, Noonan syndrome, Ochoa syndrome (urinary tract face syndrome (urofacial syndrome), nephrohydrosis) with eccentric facial expression, oculo cerebro renal syndrome, Pallister-Killian syndrome, PW, Proteus syndrome, pears shape abdomen syndrome, Rett syndrome, Robinow syndrome, rubinstein's syndrome, fissure, left and right sides transposition, Shi-Lun-Ao three Cotards, Smith-Magenis syndrome, Si Teji-weber two Cotards, congenital syphilis, trichothiodystrophy, triple X female, 13 trisomys (handkerchief tower syndrome), 9 trisomys, Turner syndrome, conjoined twins, usher syndrome, Waardenburg's syndrome, werner's syndrome or Wolf-Hirschhorn syndrome.
In some embodiments, the invention provides and be used for the treatment of individual connective tissue disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, anti-infective, the treatment metabolic disease of compound of the present invention and cancer therapy drug, immunomodulator, treatment skin disorder, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, connective tissue disease comprises ankylosing spondylitis, Ehlers-Danlos syndrome, Heng Nuo-permitted Lan Shi purpura, mucocutaneous lymphnode syndrome, Marfan syndrome, polyarteritis nodosa, polymyositis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, scleroderma, sjogren syndrome, xeropthalmus, Still disease, systemic lupus erythematous, takayasu's disease or Wegner granulomatosis.
In some embodiments, the invention provides and be used for the treatment of individual metabolic disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment kidney of medicine, anti-infective, the treatment liver of medicine, the treatment central nervous system of medicine, the treatment skin disorder of compound of the present invention and antidiabetic drug, treatment gastro-intestinal system, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, metabolic disease comprises acid base imbalance, oxypathy, alkalosis, alkaptonuria, α-mannosidosis, inborn error of amino acid metabolism, amyloidosis, hypoferric anemia, ascorbic acid deficiency, vitamin deficiency, vitamin B1 deficiency, vitamin H acid amides enzymatic defect, carbohydrate lacks glycoprotein syndrome, poison alkali disease disease (carnitine disorders), cystinosis, cystinuria, dehydration, Fabry disease, the Fatty Acid Oxidation obstacle, fucosidosis, galactosemia, Gaucher disease, Gilbert disease, glucosephosphate dehydrogenase deficiency, glutaric acidemia, glycogenosis, the Hartnup disease, hemochromatosis, hemosiderosis, hepatolenticular degeneration, histidinemia, homocystinuria, hyperbilirubinemia, hypercalcemia, hyperinsulinemia disease, hyperpotassemia, hyperlipidaemia, hyperoxaluria, hypervitaminosis A, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, low phosphoric acid ester fermentemia, insulin resistant, iodine deficiency, iron overload, chronic idiopathic jaundice, Leigh disease, HGPRT deficiency, the leucine metabolic disturbance, lysosomal storage disease, magnesium deficiency, maple syrup urine disease, Melas syndrome, door Kai Shi Menkes, metabolic trouble, metabolism syndrome X, inborn errors of metabolism, mitochondrial disease, the mucolipid accumulation is sick, the mucolipid accumulation is sick, Niemann-Pick disease, obesity, ornithine transcarbamylase deficiency, osteomalacia, pellagra, the peroxysome imbalance, phenylketonuria, red blood corpuscle generative nature porphyria, porphyria, false early ageing, Gaucher disease, refsum, Reye syndrome, rickets, sandhoff disease, hungry, Tangier, Tay Sachs disease, tetrahydrobiopterin lacks, front three aminuria disease (trimethylaminuria), tyrosinemia, urea cycle disorder, the water-electrolyte balance imbalance, Wernicke encephalopathy, vitamin A deficiency, vitamin B12 deficiency, Vitamin B deficiency, primary familial xanthomatosis or Zellweger syndrome.
In some embodiments, the invention provides and be used for the treatment of individual environmental factors and induce an illness (disorder of environmental origin), reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment kidney of medicine, anti-infective, the treatment liver of medicine, the treatment central nervous system of medicine, the treatment skin disorder of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment medicine for cardiovascular system, treatment gastro-intestinal system, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, environmental factors induces an illness and comprises barotrauma, bite and sting wound, cerebral concussion, burn, centronucleus syndrome, craniocerebral injury, electric burn, fracture, frostbite, heat stress obstacle, motion sickness, occupational illness, poisoning, SBS, shoulder injury, space sport disease, Spinal injury, tick paralysis or wound (connectivity and non-connectivity).
In some embodiments, the invention provides and be used for the treatment of individual behavioral mechanism disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises that to individual administration composition described composition comprises medicine, VITAMIN or their combination of the medicine of compound of the present invention and treatment cardiovascular systems, the medicine for the treatment of central nervous system, gene therapeutic agents, treatment endocrine system.In one embodiment, the behavioral mechanism disease comprises attack, the attitude to death, common dependence, autolesionism, sexual behaviour or social behavior.
In some embodiments, the invention provides and be used for the treatment of the individual spirit obstacle, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises that to individual administration composition described composition comprises compound of the present invention and treats medicine, VITAMIN or their combination of the medicine of central nervous system, gene therapeutic agents, treatment endocrine system.In some embodiments, mental disorder comprises A Sipeige syndrome, how moving the attention deficit disorder companion is, how moving the attention deficit disorder companion is, bipolar disorder, borderline personality disorder, Capgras syndrome, behavior disorder of children, war neurosis, the cyclothymia obstacle, the dependent personality disorder, dysthymia disorders, the divergence type mental disorder, dysthymic disorder, eating disorder, firesetting behavior, hypochondriasis, impulse control disorder, Kleine-Levin syndrome, mental disorder, the mental disorder of Childhood diagnosis, multiple personality disorder, Mi Xiaosen syndrome, Munchhausen syndrome, act on behalf of Mu﹠4﹠nchausen syndrome (Munchhausen byproxy), narcissistic personality disorder, hypnolepsy, compulsive disorder, parasexuality, phobia, psychosis, restless leg syndrome, schizophrenia, seasonal affective disorder, sexual desire and sex expression obstacle, psychological sexual dysfunction, somnopathy, body type obstacle, posttraumatic stress disorder, material dependency obstacle, suicide or trichotillomania.
In one embodiment, the disease of " depression " reference and health, mood and thinking, the idea that it influences the mode that the people has a meal, sleeps, self-perception and considers the mode of things.Depressed S﹠S comprise shortage activity interest, anorexia or excessive eating, shortage expression, hollow, sensation is desperate, pessimistic, guilty or helpless, social activity is shunk back, fatigue, somnopathy, concentrate, remember or make decision difficult, restless, irritability, headache, gastricism or chronic pain.
In one embodiment, " cognition " points out the process of knowledge, particularly keeps the process of clear-headed, understanding, thinking, study and judgement.Cognition relates to psychology, linguistics, computer science, neuroscience, mathematics, ethology and philosophy field.In one embodiment, " mood " refers to the temper or the mental status.As referred to herein, change point out know and/or mood any actively or passive the variation.
In some embodiments, the invention provides the individual hepatopathy of treatment, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, anti-infective, the treatment liver of compound of the present invention and anticarcinogen, immunomodulator, treatment gastro-intestinal system, medicine, VITAMIN or their combination of treatment endocrine system.In one embodiment, hepatopathy comprises liver cancer, primary biliary cirrhosis, autoimmune hepatitis, chronic hepatopathy, liver cirrhosis, hepatitis, viral hepatitis (hepatitis A, hepatitis B, chronic hepatitis B, hepatitis C, chronic hepatitis C, hepatitis D, hepatitis E, hepatitis X), liver failure, jaundice, pedicterus, hepatoma, liver cancer, liver abscess, alcoholic liver disease, hemochromatosis, hepatolenticular degeneration, portal hypertension, primary sclerosing cholangitis, sarcoidosis, tapeworm, hydatid disease,alveolar, fascioliasis, schistosomicide, Gaucher disease, Zellweger syndrome, alcoholism, food poisoning, pneumococcal pneumonia or halophilic vibrio.
In some embodiments, the invention provides and be used for the treatment of individual kidney disease, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment metabolic disease of medicine, anti-infective, the treatment kidney of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment gastrointestinal system, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, ephrosis comprises acromegaly, acute renal failure (ARF) (amyloidosis), the autosomal dominant multicystic kidney disease, urinary stone disease, the kidney tumour, the autosomal recessive multicystic kidney disease, chronic renal failure (CRF), chronic nephropathy, CLS, cor pulmonale, cryoglobulinemia, diabetic nephropathy, hyperlipemia, Gaucher disease, glomerulonephritis, Goodpasture, hemolytic uremic syndrome, hepatitis, kidney, urinary stone disease, leukemia, hyperlipoproteinemia, lupus, multiple myeloma, ephritis, many arterialness renal cyst (polyartekidney cysts), post-streptococcal glomerulonephritis, glomerulonephritis, nephralgia, preeclampsia, renal tuberculosis, pyelonephritis, the renal tubular acidosis ephrosis, the toxic shock syndrome that suis caused, thromboembolism, toxoplasmosis, urinary tract infection, vesicoureteral reflux or williams syndrome.
In one embodiment, described kidney disease or illness are acute, perhaps are chronic in another embodiment.In one embodiment, wherein can use the clinical indication of the kidney disease of described methods of treatment or illness to comprise glomerular filtration rate(GFR or other renal function index of cylinderuria, measurement.
In one embodiment, method of the present invention is used for easily suffering from the individuality of kidney disease or illness.In one embodiment, about the synonym that the phrase of individuality " is easily suffered from kidney disease or illness " and phrase " is in the individuality of risk ", it comprises and is in the risk of suffering from acute or chronic renal failure, if or estimate that reasonably described individuality will suffer from renal function the carrying out property loss relevant with the loss of carrying out property of the functional nephron, then described individuality is in the risk that needs the kidney alternative medicine.Whether concrete individuality is in risk is the decision that can be made routinely by the those of ordinary skill of relevant medical or veterinary field.
In one embodiment, the individuality of suffering from ephrosis, particularly suffer from the male individual of end-stage renal disease (ESRD) and suffer from hypogonadism, some of them suffer from the moderate that occurs together to severe energy-protein malnutrition (PEM), it causes higher erythropoietin (EPO) requirement, the mortality ratio of lower quality of life (QOL) mark and Geng Gao.Many people have other symptom relevant with hypogonadism, comprise fatigue, lack appetite, myasthenia etc.In some embodiments, methods of treatment of the present invention is used for the treatment of the symptom relevant with hypogonadism, and described hypogonadism is caused by women's hypoandrogenism (ADIF) in described individuality; Cause by elderly men hypoandrogenism (ADAM) (comprising that fatigue, depression, sexual desire reduction, erective dysfunction, cognitive decline, mood descend); Cause by hypoandrogenism (sex), hypoandrogenism (sex).
In one embodiment, diabetic nephropathy is the complication of diabetes, and it makes progress very early, usually before the clinical diagnosis of making diabetes.The clinical evidence that ephrosis becomes the earliest is the albumin (Microalbuminuria) that occurs low (but unusual) level (＞30mg/ days or 20 μ g/min) in the urine, then is the proteinuria (＞300mg/24h or 200 μ g/min) that continues 10-15.The type 1 diabetes patient, diabetic hypertension is just fairly obvious before patient suffers from Microalbuminuria or when patient suffers from Microalbuminuria usually.Become in case tangible ephrosis occurs, glomerular filtration rate(GFR (GFR) descended in for some time (may be several years), caused the end-stage renal disease (ESRD) of diabetic individual.
Hypertension is that the another kind of nephropathy is total to cause of disease element.In some embodiments, treat according to the present invention nephropathy can comprise with compound of the present invention and the treatment hypertensive medicament carry out synchronous therapeutic.
In some embodiments, the invention provides and be used for the treatment of individual wasting diseases, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastrointestinal system of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems, medicine, VITAMIN or their combination of treatment endocrine system.In some embodiments, wasting diseases comprises muscle injury, laid up, fixing, nerve injury, neuropathy, diabetic neuropathy, alcoholic neuropathy, subacute combined degeneration of spinal cord, diabetes, rheumatoid arthritis, motor neurone disease, duchenne muscular dystrophy, carpal tunnel syndrome, chronic infection, tuberculosis, Addison disease, adult spinal muscular atrophy (sma), limbs myatrophy, alcoholic neuropathy, apocleisis, anorexia nervosa, the apocleisis relevant with emaciation, the apocleisis relevant with aging, postmediastinum tumour (back tumour), dermatomyositis, the hip joint cancer, inclusion body myositis, incontinentia pigmenti, intercostal neuralgia, juvenile rheumatoid arthritis, LCP, myatrophy, multifocal motor neuropathy becomes, nephrotic syndrome, osteogenesis imperfecta, poliomyelitis later stage syndrome, the rib tumour, Duchenne-Arandisease, reflex sympathetic dystrophy syndrome or Tay Sachs disease.
In this article, expendable illness or obstacle definition are for being the illness or the obstacle of feature with unusual the carrying out property loss of body weight, organ quality or liver mass at least in part.The expendable illness can be used as disease for example cancer the result and take place, or be attributable to physiology or metabolism state, for example give up and use sexual maladjustment, described uselessly can take place because of long-term bed or when four limbs (for example in casting mold) times that is fixed with sexual maladjustment, or take place because of a plurality of wounds (comprising the amputation and other illness that for example in diabetes, occur) occurring, person of skill in the art will appreciate that this point.The expendable illness also can be that the age is relevant.The feature of losing weight that takes place in the expendable disease processes can be the minimizing of TBW or organ weight's minimizing, for example owing to the bone amount of tissue protein minimizing or the minimizing of muscle mass.
In one embodiment, term " myatrophy (muscle wasting) " or " myatrophy (muscularwasting) " refer to the carrying out property loss of muscle mass and/or the decay of carrying out property and the degeneration of muscle, comprise the skeletal muscle of controls movement or the cardiac muscle and the unstriated muscle of voluntary muscle and control heart.In one embodiment, described myatrophy illness or obstacle are chronic myatrophy illness or obstacle." chronic myatrophy " is defined as the chronic progressive external decay of chronic (promptly continue a very long time) the carrying out property loss of muscle mass and/or muscle mass in this article and degenerates.
The muscle mass loss that takes place in the myatrophy process can be with the mytolin decomposition that causes owing to mytolin katabolism or be degraded to feature.Protein catabolism takes place because of the protein synthesis of unusual high speed protein degradation, unusual low speed or this combination of two kinds.Be the mytolin katabolism that causes of protein degradation or low protein synthesis by height or consume the minimizing and the myatrophy that all can cause muscle mass.Term " katabolism " has the implication of generally knowing in this area, is meant the metabolism of energy burning form especially.
Myatrophy can be used as the result of symptom, disease, illness or obstacle (comprise the disease by method of the present invention treatment, for example whole latter stage renal failure) and takes place.
In some embodiments, the invention provides the method that is used to prevent statin inductive rhabdomyolysis.In some embodiments, the invention provides and be used to prevent statin inductive rhabdomyolysis, organ failure or Insufficient method.In some embodiments, the invention provides and be used to prevent statin inductive renal failure or liver failure or infull method.In one embodiment, described method comprises the composition that comprises compound of the present invention and statin to individual administration.
In one embodiment, described wasting diseases is individual emaciation or unwillingly loses weight.In another embodiment, the invention provides the amyotrophic method that is used for the treatment of, prevents, suppresses, reduces or suppress the individuality of suffering from nephropathy.In another embodiment, the invention provides the method that is used for the treatment of, prevents, suppresses, reduces or suppress the protein catabolism of the individuality of suffering from kidney disease or illness.
Emaciation be cause by disease or as the weakness of disease side reaction with lose weight.Because i or I and be in hospital for a long time or giving up of for example taking place when limbs are fixed also can cause myatrophy with sexual maladjustment.Studies show that, among the patient who suffers from damage, chronic disease, burn, wound or cancer who is in hospital for a long time, long-term one-sided myatrophy and losing weight of causing thus occur.Nervous system injury, for example the Spinal injury of the further narration of this paper also may be paathogenic factor.
In some embodiments, the invention provides and be used for the treatment of individual wasting diseases or illness, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In another embodiment, described wasting diseases and illness especially comprise: a) acquired immune deficiency syndrome (AIDS) (AIDS) consumes; B) with the relevant consumption of lying up; C) exessive appetite and/or the consumption relevant with exessive appetite; D) emaciation; E) cancer cachexia; F) HIV consumes; G) slimming emaciation and the protein loss that causes by following factor: for example voracious disease of secular critical illness, pulmonary dysfunction, respirator dependence, aging, AIDS, wound, congestive heart failure, myocardosis, burn, cancer, chronic obstructive pulmonary disease (COPD), eating disorder, anorexia nervosa, anorexia, hunger and/or depressed.
In some embodiments, the invention provides and be used for the treatment of individual disarmed state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described disarmed state is a poliomyelitis later stage syndrome.In one embodiment, described method comprises to individual administration composition, and described composition comprises medicine, the gene therapeutic agents of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastrointestinal system of compound of the present invention and immunomodulator, antidiabetic drug, treatment cardiovascular systems, medicine, VITAMIN or their combination of treatment endocrine system.
In some embodiments, the present invention provides assisting therapy with compound of the present invention.For example, in one embodiment, in disease, obstacle or treatment of conditions (wherein use and take exercise and dietary restriction), administration compound of the present invention is included in this treatment plan.For example, in one embodiment, to be familiar with as those skilled in the art, adjuvant therapy or the treatment carried out with compound of the present invention, in conjunction with dietary restriction and/or exercise, may be used for the treatment of insulin resistant, glucose intolerance, lose weight, the therapy of diabetes, cardiovascular disorder, metabolism syndrome, cancer, myatrophy etc.
In some embodiments, the invention provides and be used for the treatment of individual hypogonadism state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the invention provides and be used for the treatment of individual pharmacological agent inductive hypogonadism state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In some embodiments, hypogonadism is caused that by treatment described treatment changes the secretion of hormone from women and male gonad.In some embodiments, hypogonadism may be " idiopathic " or " central ".In primary hypogonadism disease, ovary or testis itself plays a role undesiredly.In some embodiments, hypogonadism may be by surgical operation, radiation, heredity illness and dysplasia, hepatopathy and ephrosis, infection or some auto-immune disease inductive.In some embodiments, menopause is the form of hypogonadism.In some embodiments, the menopause irritability that may cause amenorrhoea, hot flush, vagina drying or descend owing to women estrogen level.In one embodiment, described method comprises to individual administration composition, and described composition comprises the medicine, anti-infective, the medicine of treatment liver, medicine, VITAMIN or their combination of treatment kidney of medicine, the treatment skin disorder of medicine, gene therapeutic agents, the treatment endocrine system of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastro-intestinal system of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems.
In some embodiments, the invention provides and be used for the treatment of individual osteopenia state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the invention provides and be used for the treatment of individual pharmacological agent inductive osteopenia state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In some embodiments, osteopenia is the slight minimizing of bone amount.In some embodiments, osteopenia is the omen of osteoporosis.In some embodiments, osteopenia is defined as the bone density than normal young adult's low 1-2.5 the standard deviation (SD) of bone density.In one embodiment, described method comprises to individual administration composition, and described composition comprises the medicine, anti-infective, the medicine of treatment liver, medicine, VITAMIN or their combination of treatment kidney of medicine, the treatment skin disorder of medicine, gene therapeutic agents, the treatment endocrine system of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastro-intestinal system of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems.
In some embodiments, the invention provides and be used for the treatment of individual few flesh state, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, the invention provides and be used for the treatment of the few flesh state of individual pharmacological agent inductive, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.Sarcopenia is that serious muscle mass reduces in some embodiments.In one embodiment, the definition of Sarcopenia is to have than 2 lower lean masses of standard deviation of the mean value that is lower than normal young adult.In some embodiments, Sarcopenia is caused by following reason: inherited genetic factors, the recycle system changes, kapillary: the myofiber ratio reduces, motor neuron changes, denervation, the decline of motor nerve ending plate, I fiber type selective yeinnervation, cause the inflammatory response of muscle damage, hypokinesis, malnutritive, low dietary protein intake, vitamin D deficiency, age, relevant vitamins D reduced, oxidative stress, the muscle mitochondrial mutations, the myofibrillar change of particular type, mytolin reduces, disabling disease, palsy, Alzheimer, Parkinson's disease, osteoporosis, atherosclerosis, diabetes, hyperinsulinemia, renal failure or hypogonadism.In one embodiment, described method comprises to individual administration composition, and described composition comprises the medicine, anti-infective, the medicine of treatment liver, medicine, VITAMIN or their combination of treatment kidney of medicine, the treatment skin disorder of medicine, gene therapeutic agents, the treatment endocrine system of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastro-intestinal system of SARM compound and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems.
In some embodiments, the invention provides the combination that is used for the treatment of individual disease as indicated above and/or illness, reduce its sickness rate, delay its outbreak or progress or alleviate and/or eliminate the method for relative symptom.In one embodiment, described method comprises to individual administration composition, and described composition comprises the medicine, anti-infective, the medicine of treatment liver, medicine, VITAMIN or their combination of treatment kidney of medicine, the treatment skin disorder of medicine, gene therapeutic agents, the treatment endocrine system of medicine, the treatment wasting diseases of medicine, the treatment metabolic disease of medicine, the treatment central nervous system of medicine, the treatment gastro-intestinal system of compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, treatment cardiovascular systems.
Should be appreciated that of the present invention any method as described herein all comprises to individual administration compound as herein described or comprises its composition, with disease, obstacle or the illness of treatment indication.Each method as herein described and/or its all also may comprise administration other therapeutical agent as herein described, person of skill in the art will appreciate that this point.
In some embodiments, the invention provides and be used to promote for example method of the generation of breast, sperm or ovum.In some embodiments, the invention provides the method for the generation that is used to promote lean meat or ovum.In some embodiments, the invention provides and be used to improve the method for productivity of feeding or breeding livestock, for example increase sperm count, improve sperm morphology etc.In some embodiments, the invention provides production phase that is used to prolong farm-animals (for example bird inlay, milk cow etc. gives milk) and/or the method that improves herd health (for example improving immune clearance, strong animal).
In one embodiment, described method comprises that to individual administration composition, described composition comprises compound of the present invention and anticarcinogen, immunomodulator, antidiabetic drug, the medicine of treatment cardiovascular systems, the medicine of treatment gastro-intestinal system, the medicine of treatment central nervous system, the medicine of treatment metabolic disease, the medicine of treatment wasting diseases, gene therapeutic agents, the medicine of treatment endocrine system, the medicine of treatment skin disorder, anti-infective, the medicine of treatment liver, the medicine of treatment kidney, VITAMIN, nutritional additive, hormone (each and/or all as described herein), or any other therapeutical agent as described herein, or their combination.
In another embodiment, the invention provides the method that is used for the treatment of individual following disease: cystic fibrosis and descend, drink and smoking inductive osteoporosis by its inducibility hypogonadism state that causes, epilepsy and by its inducibility hypogonadism shape that causes and/or hypermetabolism state, hereditary angiodysplasia, lupus erythematosus and by its BMD that causes, described method comprises to described individual administration SARM as herein described.
In another embodiment, the invention provides the method that is used for the treatment of individual following disease: syndrome and other disarmed state, statin inductive rhabdomyolysis, statin inductive myasthenia, statin inductive organ failure or functional defect after poliomyelitis and the poliomyelitis, described method comprises administration compound as herein described and optional suitable statin (originally person of skill in the art will appreciate that this point), and/or any therapeutical agent.
In another embodiment, the invention provides the method that is used for the treatment of opioid inductive hypoandrogenism (OPIAD), described method comprises to individual administration compound as herein described and opiate randomly, opioid, narcotic etc., methadone, long-acting opiate/opioid is Kadian for example, slowly-releasing morphine (all opiate/opioids/narcotic all obtains the FDA approval), opiate/the opioid that is used for the treatment of heroin addiction, opiate/the opioid that is used for the treatment of the malignant tumour chronic pain, opiate/the opioid that is used for the treatment of the chronic pain syndrome of non-malignant tumors.
In another embodiment, the invention provides the method that is used for the treatment of nervous system disorders, obstacle or illness, described method comprises to described individual administration compound as herein described and optional antipsychotic drug (for example zotepine, haloperidol, amisulpride, risperidone, other dopamine D 2 receptor antagonists), anti-epileptic medicine (for example valproic acid, Carbamzepine, oxcarbazepine (oxcarbamazepine) etc.) or their composition.
In another embodiment, the invention provides the method that is used for the treatment of hormone-dependent diseases, obstacle or illness, described method comprises to described individual administration compound as herein described and randomly chemotherapeutics and treatment (methotrexate, endoxan, ifosfamide, Zorubicin, Dx, glucocorticosteroid, S-Neoral, Levothyroxinnatrium, SERM, antiphlogiston, fulvestrant, GnRH agent, ADT, termination Hormone Replacement Therapy, cranium cerebral radiation, periphery irradiation (peripheral irradiation) etc.; (the serotoninergic antidepressive by the 5HT2 receptor acting, selective serotonin reuptake inhibitor, oxidase inhibitor, tricyclic antidepressants, antihypertensive drug be methyldopa, serpentine, clonidine and verapamil for example to induce the pharmacological agent of hyperprolactinemia (prolactinemia); The antiemetic of dopamine antagonist is metoclopramide for example, and bisfentidine is Cimitidine Type A/AB and Ranitidine HCL for example, oestrogenic hormon, amphetamine, AR partial antagonist (KETOKONAZOL, spironolactone, eplerenone)
In another embodiment, compound of the present invention and composition as described herein are used for promoting or quicken recovering behind the operation technique.
In one embodiment, the invention provides the purposes that compound as herein described is used to reduce individual fat quantity.In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination or contain this using method of their composition.
In another embodiment, the invention provides compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination or contain the following purposes of their composition: the accumulation of treatment stomach fat; Treatment obesity-related Sarcopenia; Improve body composition; Reduce body fat content; Reduce fat quantity; Improve plasma lipid profile (profile), increase muscle mass/muscle strength/muscle function; Increase bone amount/BMD/ bone strength/bone function; Reduce body fat; Congenital hyperinsulinemia; Hypercortisolism (high hydrocortisone mass formed by blood stasis (hypercortisolemia)); Individual obesity or the diabetes relevant with metabolism syndrome.
In another embodiment, described individuality suffers from hormonal imbalance, hormone illness or hormone disease.In another embodiment, described individuality is in menopause.
In one embodiment, the invention provides the purposes that compound as herein described is used to increase individual lean mass.In another embodiment, this purposes comprises administration compound as herein described or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination.
In one embodiment, described individuality suffers from hormonal imbalance, hormone illness or hormone disease.In another embodiment, described individuality is in menopause.
Embodiment 15 shows that the compound of formula (I) is an anabolism, but its male sex hormone is minimum, and therefore, it is incompatible patient group that this compound can be used for the treatment of the past male sex hormone.No matter whether testosterone exists, and the compound of formula (I) all shows the promotion muscle growth, simultaneously prostate gland is applied antiproliferative effect, and therefore, in one embodiment, method of the present invention is used to recover to suffer from the muscle mass of Sarcopenia or cachectic bulk diffusion.
In one embodiment, compound as herein described changes individual leptin level.In another embodiment, compound as herein described reduces the level of leptin.In another embodiment, compound as herein described increases individual leptin level.Known leptin to the appetite of obesity mouse, lose weight influentially, so it is relevant with obesity.
In one embodiment, the cyclical level of compounds affect leptin as herein described in another embodiment, influences the level of organizing of leptin.In one embodiment, term " level of leptin " refers to the serum level of leptin.As referred to herein, compound of the present invention is influential to external and intravital leptin.The level of leptin can be measured with method known to those skilled in the art, for example measures by commercially available ELISA test kit.And, the level of mensuration leptin in can in external test or body, measuring by any method known to those skilled in the art.
Since leptin with control appetite, lose weight, pickuping food is relevant with energy expenditure, so, regulate and/or the level of control leptin is treatment, prevention, the inhibition obesity of suffering from the obesity individuality, the useful methods of treatment that reduces its sickness rate.The level of regulating leptin can cause lacking the energy expenditure of appetite, minimizing ingestion of food, increase leptin individuality, therefore, has control of being beneficial to and treatment of obesity.
In one embodiment, term " obesity " is defined as by fat excessive accumulation in health and causes weight increase to surpass the restriction of bone and the needs of health
In one embodiment, term " obesity relevant Metabolic disorder " refer to cause by obesity, as the consequence, that increase the weight of because of obesity of obesity or be secondary to the illness of obesity.The nonrestrictive example of this illness is osteoarthritis, type ii diabetes, blood pressure increase, palsy and heart trouble.
Cholesterol, triglyceride and other lipid transport in body fluid by lipoprotein, and described lipoprotein can be divided into for example vldl (VLDL), intermediate density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) (HDL) according to their density.
Show that the high level of LDL-cholesterol in blood is relevant with atherosclerosis, atherosclerosis is the PD that partly is deposited as feature with lipid in artery inwall particularly coronarius.And shown that also the high blood levels of LDL-cholesterol is relevant with coronary heart disease.And, there is negative correlation between the blood levels of HDL cholesterol and the coronary heart disease.
Total cholesterol level in the blood (it is the summation of HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol and chylomicron-cholesterol) is the omen of coronary heart disease and atherosclerosis risk not necessarily.
But the association between atherosclerosis and the LDL cholesterol levels is more much higher than the similar association between atherosclerosis and the total serum cholesterol levels.
In one embodiment, the invention provides the using method that compound as herein described is used to improve individual lipodogramme and/or reduces the circulation lipid level.In some embodiments, according to this aspect of the invention, described individuality is suffered from and is selected from one or more following illnesss: atherosclerosis and relative disease thereof, cross presenility, Alzheimer, palsy, toxic hepatitis, viral hepatitis, peripheral vascular insufficiency, ephrosis and hyperglycemia, and the present invention is used for administration compound as herein described or contains its composition, in some embodiments, described compound or composition influence the lipodogramme of described individuality energetically, and this is the disease that described method is used for the treatment of indication, a kind of means of obstacle and illness.
In one embodiment, the invention provides treatment arteriosclerosis and relative disease, for example cardiovascular disorder, cerebrovascular disorder, surrounding blood vessel illness, vascular disease of bowel disease or their combination.
In one embodiment, cardiovascular disorder comprises hypertension (HTN), coronary artery disease (CAD) or heart muscle perfusion.In another embodiment, the invention provides the using method that SARM compound as herein described is used to promote aortic smooth muscle cell propagation.In another embodiment, the invention provides compound as herein described and be used for the treatment of atherosclerotic using method.In another embodiment, the invention provides the using method that compound as herein described is used to bring high blood pressure down.In another embodiment, the invention provides the using method that compound as herein described is used for the treatment of heart disease and illness (comprising for example myocardial infarction, cardiac hypertrophy and congestive heart failure of myocardosis, cardiac insufficiency (cognitive heartfailure)).In another embodiment, the invention provides the user that compound as herein described is used for protecting heart (being included in the protection heart of insulin resistant); Treatment I type and type ii diabetes, metabolism syndrome, X syndrome and/or hypertensive using method.
In one embodiment, the invention provides the method that is used for the treatment of, prevents individual cardiovascular and/or cerebrovascular disease, reduces its mortality risk, described method comprises compound or its prodrug, analogue, isomer, meta-bolites, derivative, pharmacy acceptable salt, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or their arbitrary combination of Medicine-feeding type (I) or contains their pharmaceutical composition.In one embodiment, described compound is a feature with the structure of formula (I).
In one embodiment, the compound of formula I reduces the level of LDL and total cholesterol.In another embodiment, the compound of formula (I) reduces the individual LDL and the level of total cholesterol.
In another embodiment, the medicament Combined Preparation of the compound of formula I and rising HDL.In another embodiment, the medicament Combined Preparation of the compound of formula (I) and rising HDL.In another embodiment, the medicament of rising HDL comprises nicotinic acid.In another embodiment, the medicament of described rising HDL comprises the special class of shellfish, and the special class of described shellfish comprises that gemfibrozil (Lopid), thiocarbamide are gemfibrozil analogue and fenofibrate (TriCor).In another embodiment, the medicament of rising HDL comprises statins.In another embodiment, the medicament of rising HDL comprises 1-hydroxyalkyl-3-benzene thiocarbamide and analogue thereof.
In one embodiment, the invention provides the method that is used to reduce individual circulation lipid level, described method comprises compound or its pharmacy acceptable salt, hydrate, N-oxide compound or their arbitrary combination of Medicine-feeding type I or contains their composition.In one embodiment, described individuality is suffered from atherosclerosis and relative disease thereof, is crossed presenility, Alzheimer, palsy, toxic hepatitis, viral hepatitis, peripheral vascular insufficiency, ephrosis, hyperglycemia or their arbitrary combination.
In one embodiment, the invention provides and be used for the treatment of the individual atherosclerosis and the method for relative disease (for example cardiovascular disorder, cerebrovascular disorder, surrounding blood vessel illness or vascular disease of bowel disease) thereof, described method comprises to the compound of described individual Medicine-feeding type I or its pharmacy acceptable salt, hydrate, N-oxide compound or their arbitrary combination or contains the step of their composition.Described method can also comprise simultaneously, subsequently or known one or more medicaments that can be used for treating cardiovascular disorder, cerebrovascular disorder, surrounding blood vessel illness or vascular disease of bowel disease of administration formerly.
In one embodiment, the invention provides and improve the individual handiness and the method for motion, for example by treating the sacroiliitis of described individuality.
In another embodiment, term " sacroiliitis " refers to mainly occur in the non-inflammatory osteoarthritis among the elderly, and it is a feature with joint cartilage sex change, bone and edge hypertrophy, synovial membrane change etc.In another embodiment, it is also with pain and stiff, particularly after long-term activity.
In one embodiment, term " diabetes " refers to lacking relatively or definitely of Regular Insulin, causes uncontrolled carbohydrate metabolism.Most patients can be divided into clinically suffers from insulin-dependent diabetes mellitus (IDDM or type i diabetes) or non insulin dependent diabetes (NIDDM or type ii diabetes).
In other embodiments, term " blood pressure increase " or " hypertension " refer in the repeated hypertension that surpasses 90/140mmHg.Chronic hypertension can cause optical fundus blood vessel to change, cardiac muscle thickens, renal failure and cerebral lesion.
In other embodiments, term " palsy " refers to that described blood supply insufficiency is often caused by angiorrhexis or blood clot because blood supply insufficiency causes the cranial nerve cell infringement.In other embodiments, term " heart trouble " refers to heart normal function and the movable obstacle that takes place, and comprises heart failure.
And, show that recently male sex hormone relates to pluripotent mesenchymal cell and is fixed to the muscle-derived pedigree and stops and be divided into into fat pedigree people such as (, Endocrinology, 2003, July 24) Singh.Therefore, described compound can be used for the method for prevention steatogenesis as herein described and/or change differentiation of stem cells.
In another embodiment, the present invention relates to quicken, increase or promote individual slimming method, described method to comprise to described individual administration effectively quickens, increases or promote the compound as herein described of the slimming amount of described individuality and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to reduce, suppress, suppress or reduce the method for individual appetite, described method comprises to described individual administration and effectively reduces, suppresses, suppresses or reduce the compound as herein described of amount of appetite of described individuality and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to change the method for individual body composition, described method comprises to the compound as herein described of the amount of the body composition of the described individuality of the effective change of described individual administration and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.In one embodiment, change described body composition and comprise lean mass, fat free body weight or their combination that changes described individuality.
In another embodiment, the present invention relates to change the individual lean mass or the method for fat free body weight, described method comprises to described individual administration and effectively changes the lean mass of described individuality or go the compound as herein described of amount of fat body weight and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to the fat of individuality is converted into the method for thin muscle, described method comprises to described individual administration and effectively the fat of described individuality is converted into the compound as herein described of amount of thin muscle and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to treat the method for the relevant Metabolic disorder of individual obesity, described method comprises to the compound as herein described of the amount of the relevant Metabolic disorder of the obesity of the described individuality of the effective treatment of described individual administration and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to prevent, suppress, suppress or alleviate the method for the relevant Metabolic disorder of individual obesity, described method comprises to described individual administration effectively to be prevented, suppress, suppresses or alleviate the compound as herein described of amount of the relevant Metabolic disorder of individual obesity and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In one embodiment, the Metabolic disorder that described obesity is relevant is a hypertension.In another embodiment, described illness is an osteoarthritis.In another embodiment, described illness is a type ii diabetes.In another embodiment, described illness is that blood pressure increases.In another embodiment, described illness is a palsy.In another embodiment, described illness is a heart trouble.
In another embodiment, the present invention relates to reduce, suppress, suppress or reduce individual adipogenic method, described method comprises the step to described individual administration compound as herein described and/or its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In another embodiment, the present invention relates to change the method for individual differentiation of stem cells, described method comprises to the compound as herein described of the amount of the differentiation of stem cells of the described individuality of the effective change of described individual administration and/or the step of its analogue, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination.
In one embodiment, compound as herein described is used for: a) treat, prevent, suppress, suppress or alleviate obesity; B) quicken, increase or promote and lose weight; C) reduce, suppress, suppress or reduce appetite; D) change body composition; E) change lean mass or fat free body weight; F) fat is converted into thin muscle; G) treat, prevent, suppress, suppress or alleviate the relevant Metabolic disorder of obesity, for example hypertension, osteoarthritis, diabetes, maturity onset diabetes of the young (MODY), blood pressure increase, palsy or heart trouble; H) reduce, suppress, suppress or reduce lipogenesis; I) change differentiation of stem cells; And/or j) changes leptin level.
In one embodiment, compound as herein described is used for the treatment of or ends the progress or the treatment diabetic symptom of diabetes.In another embodiment, compound as herein described is used for the treatment of the complication relevant with diabetes.These illnesss comprise: hypertension (HNT), cerebro-vascular diseases, coronary atherosclerotic heart disease, macular degeneration, diabetic retinopathy (illness in eye) and blind, cataract-systemic inflammatory (with inflammation index for example erythrocyte sedimentation rate or c reactive protein increase to feature), inborn defect, with PA diabetes, preeclampsia and gestational hypertension, ephrosis (renal insufficiency, renal failure etc.), sacred disease (diabetic neuropathy), shallow table and systemic fungal infection, congestive heart failure, gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia, fatty liver disease (nonalcoholic fatty liver disease or NASH), and the relevant tetter of the diabetes progressive ring of diabetes fat dead (NLD) for example, the big blister of diabetes (BD), the dermexanthesis vitiligoidea, Digital Sclerosis, DGA and acanthosis nigricans.
In one embodiment, the invention provides treatment, compacting, suppress following human individual's disease or reduce the method for its sickness rate: (a) type i diabetes; (b) type ii diabetes; (c) glucose intolerance; (d) hyperinsulinemia; (e) insulin resistant; (f) ephrosis; (g) diabetic neuropathy; (h) diabetic retinopathy; (i) fatty liver disease; (j) MODY and (k) cardiovascular disorder, described method comprises the step to the compound of described individual Medicine-feeding type (I).
In some embodiments, compound as herein described and/or the composition that comprises them can be used for the disease relevant with the individuality of suffering from diabetes or the application or the treatment of illness.In one embodiment, the individuality of seeking by method treatment of the present invention is an individuality of suffering from type i diabetes.It is feature that type i diabetes destroys with the autoimmunization of pancreatic beta cell.The immune destruction sign of described β cell appears in 90% individuality when diagnosis, described sign comprises islet cells (ICA) antibody, L-Glutamic decarboxylase (GAD) antibody and Regular Insulin (IAA) antibody.Although the diabetes of this form betide among children and the teenager usually, it can betide any age.Young individuals have usually fast the β cytoclasis and with have ketoacidosis simultaneously, and the grownup often keeps competent insulin secretion to reach many years to prevent ketoacidosis.Finally, all I type glycosuria needs of patients insulin treatments are to keep the blood sugar amount normal.
In one embodiment, the invention provides the method for treatment type ii diabetes.Type ii diabetes is feature with the insulin resistant, and is feature in certain stage of this disease incidence with the insulin secretion relative deficiency.The absolute value of plasma insulin concentration (fasting and meals stimulate) increases usually, still " with respect to " seriousness of insulin resistant, plasma insulin concentration is not enough to keep normal glucose stable state.Yet, as time passes, carrying out property beta cell failure appears, Regular Insulin absolute value deficiency then takes place.The individuality that great majority suffer from type ii diabetes show property (internal organ) obesity in the abdomen, with the closely-related fatty liver that exists of insulin resistant.Described patient's liver becomes insulin resistance, and glycogenolysis is uncontrolled, and the result is that glucose that increase, non-physiologic is transported in the blood.Cholesterol and VLDL particle that liver produces are also uncontrolled.And these individualities exist hypertension, hyperlipemia (high triglyceride level and low HDL-cholesterol level usually; Hyperlipidaemia after the meal) and the PAI-1 level raise.This a succession of " insulin resistance syndrome " or " metabolism syndrome " or relevant illness of obesity of being called as unusually.Because these are unusual, the patient of type ii diabetes suffer from the great vessels complication for example the risk of myocardial infarction and palsy increase.
In one embodiment, the invention provides the method for treatment diabetic nephropathy.Diabetic nephropathy is the complication of diabetes, and it makes progress very early, usually before the clinical diagnosis of making diabetes.The clinical evidence that ephrosis becomes the earliest is the albumin (Microalbuminuria) that occurs low (but unusual) level (＞30mg/ days or 20 μ g/min) in the urine, then is the proteinuria (＞300mg/24h or 200 μ g/min) that continues 10-15.The type 1 diabetes patient, diabetic hypertension is just fairly obvious before patient suffers from Microalbuminuria or when patient suffers from Microalbuminuria usually.Become in case tangible ephrosis occurs, glomerular filtration rate(GFR (GFR) descended in for some time (may be several years), caused the end-stage renal disease (ESRD) of diabetic individual.
In one embodiment, the invention provides the method for treatment diabetic neuropathy.Diabetic neuropathy is the nervous disorders family that is caused by diabetes.Diabetic neuropathy causes hand, arm, foot and leg numbness, causes their pain and unable sometimes.Neurological problem in the diabetes may betide each tract, comprises digestive tube, heart and sexual organ.Diabetic neuropathy is divided into peripheral neuropathy, autonomic neuropathy, the near-end DPN and focal DPN.Peripheral neuropathy causes the pain or the anesthesia of toe, foot, leg, hand and arm.The autonomy DPN causes the variation of digestion, intestines and bladder function, property reaction and perspiration, also can influence the nerve of service heart and controlling blood pressure.The near-end DPN causes thigh, hip or stern pain and causes skelasthenia.Focal DPN causes the weak suddenly of a nerve or one group of nerve, causes myasthenia or myalgia.The intravital any nerve of body all may be influenced.
In one embodiment, the invention provides the method for treatment of diabetic retinopathy.Diabetes are called diabetic retinopathy to the influence of eye.The diabetic subject more may suffer from eye illness, for example cataract and glaucoma.Diabetic retinopathy is very wide to the influence variation of vision, depends on the stage of this disease.The total symptom of some of diabetic retinopathy is that blurred vision (this is often relevant with glucose level), floating matter (floaters) and flicker (flashes) and eyesight are lost suddenly.
In one embodiment, the individuality of seeking by method treatment of the present invention is an individuality of suffering from glucose intolerance.Glucose intolerance is a pre-diabetes, and wherein, blood sugar is higher than normal level, but does not have high to guaranteeing to be diagnosed as diabetes.
In one embodiment, the individuality of seeking by method treatment of the present invention is an individuality of suffering from hyperinsulinemia.Hyperinsulinemia is the sign that causes the potential problems of pancreatic secretion excess insulin.The most general reason of hyperinsulinemia is an insulin resistant, and in this illness, your health is to the effect of synalbumin, and pancreas is attempted usually to compensate by producing more pancreas islet.Hyperinsulinemia is relevant with the II diabetes.
In one embodiment, the individuality of seeking by method treatment of the present invention is an individuality of suffering from insulin resistant.Insulin resistant is that the insufficient insulin of wherein normal amount is so that adipocyte, myocyte and liver cell produce the illness of normal insulin response.Insulin resistant in the adipocyte causes the triglyceride hydrolysis of storage, and this improves the level of free lipid acid in the blood plasma.Insulin resistant in the muscle reduces the absorption of glucose, and the insulin resistant in the liver reduces the glucose storage, and these two kinds of effects help to improve blood sugar.High-caliber plasma insulin owing to insulin resistant is that glucose often causes metabolism syndrome and type ii diabetes.
Diabetes are generally relevant with the rising of free fatty acids (FFA) level with the liver obesity, and free fatty acids promotes accumulation of lipid and the insulin resistant in the target tissue, promptly mainly weakens the effect of Regular Insulin in skeletal muscle and liver.The outstanding role of Regular Insulin is the glucose output that reduces from liver.FFA stimulates the liver glyconeogenesis, reduces parallel carrying out (compensation process that is called as " liver self adjusting ") as long as glyconeogenesis decomposes with liver starch, and glyconeogenesis itself can not cause liver glucose output to increase.FFA stimulates insulin secretion, and the secretion of Regular Insulin by glucagon suppression (glycogenolytic inductor) partly stops glycogenolysis.Yet long-term high-caliber FFA causes the liver insulin resistant, and therefore destroys liver self and regulate, and causes hepatic glucose generation increase and suffers from type ii diabetes.Fatty liver and liver insulin resistant are the main drives of hyperglycemia and type ii diabetes.
In one embodiment, the invention provides the method for inhibition (improvement) fatty liver, the insulin resistant in the described method liver is suppressed (improvement), solves the basic problem of II type Regular Insulin thus.
In another embodiment, described diabetes are type i diabetes.In another embodiment, described diabetes are type ii diabetes.
In one embodiment, the invention provides treatment, compacting, suppress the human individual diabetes, reduce the method for its sickness rate, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In another embodiment, described diabetes are type i diabetes.In another embodiment, described diabetes are type ii diabetes.
In one embodiment, the invention provides treatment and suffer from the human individual's of glucose intolerance method, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's hyperinsulinemia, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's insulin resistant, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's diabetic nephropathy, described method comprises the step to the SARM compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's diabetic neuropathy, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's diabetic retinopathy, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's fatty liver disease, described method comprises the SARM compound of described individual Medicine-feeding type I or the step of its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides the method for treatment human individual's vascular disease, described method comprises the step to the compound of described individual Medicine-feeding type I or its isomer, pharmacy acceptable salt, medicine, hydrate, N-oxide compound or their arbitrary combination.
In one embodiment, the invention provides and be used for a) treatment, prevention, compacting, suppress atherosclerosis, b) treatment, prevention, compacting, inhibition is owing to the method for the hepatic injury of fatty deposits, and described method comprises to described individual administration effectively treats, prevention or suppress atherosclerosis and owing to compound as herein described and/or its analogue of the amount of the hepatic injury of fatty deposits, derivative, isomer, meta-bolites, pharmacy acceptable salt, medicine, hydrate, the N-oxide compound, prodrug, polymorphic form, crystal or their arbitrary combination, the step that perhaps contains their composition.
In one embodiment, compound as herein described is used for: a) treat, prevent, suppress, suppress or alleviate atherosclerosis; B) treat, prevent, suppress, suppress hepatic injury owing to fatty deposits.
In one embodiment, atherosclerosis refers to the chronic complex disease that may begin from infringement artery innermost layer.In another embodiment, the reason of infringement arterial wall may comprise: a) blood cholesterol levels improves; B) hypertension; C) tobacco smoke; D) diabetes.In another embodiment, this illness of smoker is medicable, although tobacco smoke may make the atherosclerosis severe exacerbation and quicken its development in coronary artery, Aorta and leg arteries.Similarly, in another embodiment, method of the present invention can be used for the treatment of the individuality (it suffers from atherosclerotic risk increases) with cardiovascular disorder family history in one's early years.
In one embodiment, refer to that owing to the hepatic injury of fatty deposits fat accumulation in liver cell forms fatty liver, fatty liver may maybe may cause the liver inflammation with the inflammation-related of liver.This can cause cicatrization and the sclerosis of liver.When the formation of epulosis trace became popularity, it was called liver cirrhosis.
In another embodiment, fat is accumulated in liver and is become obesity.In another embodiment, fatty liver is also relevant with heavy drinking with diabetes, high blood triglyceride.In another embodiment, fatty liver may be followed for example vitamin A excessive or use some drugs such as valproic acid (trade(brand)name: Depakene/Depakote) and reflunomide (cortisone, prednisone) and taking place in the intestines bypass, body of tuberculosis and malnutritive, treatment of obesity of some disease.Sometimes fatty liver takes place as pregnancy complications.
In one embodiment, the individuality of suffering from ephrosis, particularly suffer from the male individual of end-stage renal disease (ESRD) and suffer from hypogonadism, some of them suffer from the moderate that the occurs together protein-energy malnutrition (PEM) to severe, it causes higher erythropoietin (EPO) requirement, lower QOL mark and the mortality ratio of Geng Gao.Many people have other symptom relevant with hypogonadism, comprise fatigue, lack appetite, myasthenia etc.In some embodiments, methods of treatment of the present invention is used for the treatment of the relevant symptom of hypogonadism that causes with kidney disease or illness by described individuality.
In one embodiment, diabetic nephropathy is the complication of diabetes, and it makes progress very early, usually before the clinical diagnosis of making diabetes.The clinical evidence that ephrosis becomes the earliest is the albumin (Microalbuminuria) that occurs low (but unusual) level (＞30mg/ days or 20 μ g/min) in the urine, then is the proteinuria (＞300mg/24h or 200 μ g/min) that continues 10-15.At the type 1 diabetes individuality, diabetic hypertension is just fairly obvious before patient suffers from Microalbuminuria or when patient suffers from Microalbuminuria usually.Become in case tangible ephrosis occurs, glomerular filtration rate(GFR (GFR) descended in for some time (may be several years), caused the end-stage renal disease (ESRD) of diabetic individual.
Hypertension is that the another kind of nephropathy is total to cause of disease element.In some embodiments, treat according to the present invention nephropathy can comprise with compound of the present invention and the treatment hypertensive medicament carry out synchronous therapeutic.
Can comprise that the androgen-dependent illness of method treatment of the present invention comprises and old and feeble relevant illness with compound as herein described and/or composition.In one embodiment, compound as herein described is used for: a) relevant function reduction (ARFD) of age; B) reverse or prevent ARFD; C) reverse or prevent the elderly ARFD; D) Sarcopenia or the osteopenia that reverses or prevent ARFD to cause; E) male climacteric, vasomotion male climacteric syndrome; F) mammogenesis male climacteric, muscle strength/function; G) bone strength/function; H) indignation; I) unable; J) chronic fatigue syndrome; K) cognitive impairment; And/or l) improves cognitive function.
In one embodiment, compound as herein described is used for the treatment of inflammation and associated conditions, for example: a) prevention, treatment or reverse sacroiliitis; B) prevention, treatment or reverse arthritis illness, Behcet (active immunity vasculitis) for example, bursitis, dihydroxy Calcium Pyrophosphate crystal deposition disease (or chondrocalcinosis) (CPPD), carpal tunnel syndrome, the reticular tissue illness, Crohn's disease, Ehlers-Danlos syndrome (EDS), fibromyalgia, gout, infective arthritis, inflammatory bowel (IBD), juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, systemic lupus erythematous (SLE), Lyme disease, Marfan syndrome, myositis, osteoarthritis, polyarteritis nodosa, polymyalgia rheumatica, psoriatic, psoriatic arthritis, Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, the special syndrome of Lay, rheumatoid arthritis, scleroderma, sjogren syndrome, tendinitis or ulcerative colitis; C) prevention, treatment or reverse autoimmune disorder.
In one embodiment, compound as herein described is used to prevent iatrogenic effect, comprise acute fatigue syndrome (operation back) or the side reaction of androgen-deprivation treatment (ADT) inductive, for example muscle mass minimizing, muscle strength reduction, fragility, hypogonadism, osteoporosis, osteopenia, BMD reduce and/or the bone amount reduces.
In one embodiment, described compound and/or composition and/or their using method are used for the treatment of the human individual, and wherein, in one embodiment, described individuality is the male sex, or in another embodiment, described individuality is the women.
In one embodiment, method of the present invention comprises the of the present invention compound of administration as unique activeconstituents.Yet, be used for following method and be also contained in the scope of the present invention: diabetes and associated conditions, hormonotherapy, xeropthalmus, obesity, treatment prostate cancer, the recurrence, the male contraception that delay prostatic progress and prevent and/or treat prostate cancer; The illness that treatment osteoporosis, treatment is relevant with AIDF and treat and/or prevent chronic myatrophy, described method comprises unites the described compound of one or more therapeutical agent administrations.These medicaments are including, but not limited to other SARM of: LHRH analogue, reversible androgen antagonist, antiestrogen, antitumour drug, 5-alpha reductase inhibitor, aromatase inhibitor, progestogen, medicament, selective estrogen receptor modulators (SERM), progestogen, oestrogenic hormon, PDE5 inhibitor, Apomorphine, bisphosphonate by other nuclear hormone receptor effect and one or more.
Therefore, in one embodiment, method of the present invention comprises associating diabetes medicament (for example troglitazone, rosiglitazone and pioglitazone) administration compound of the present invention.In another embodiment, method of the present invention comprises the described compound of associating LHRH analogue administration.In another embodiment, method of the present invention comprises the described compound of associating reversible androgen antagonist administration.In another embodiment, method of the present invention comprises the described compound of associating antiestrogen administration.In another embodiment, method of the present invention comprises the described compound of associating anticarcinogen administration.In another embodiment, method of the present invention comprises the described compound of associating 5-alpha reductase inhibitor administration.In another embodiment, method of the present invention comprises the described compound of associating aromatase inhibitor administration.In another embodiment, method of the present invention comprises the described compound of associating progestogen administration.In another embodiment, method of the present invention comprises the described compound of medicament administration of uniting by other nuclear hormone receptor effect.In another embodiment, method of the present invention comprises the described compound of combined selective estrogenic agents (SERM) administration.In another embodiment, method of the present invention comprises the described compound of associating progesterone administration.In another embodiment, method of the present invention comprises the described compound of associating oestrogenic hormon administration.In another embodiment, method of the present invention comprises the described compound of combined PD E5 inhibitor administration.In another embodiment, method of the present invention comprises the described compound of associating Apomorphine administration.In another embodiment, method of the present invention comprises the described compound of associating bisphosphonate administration.In another embodiment, method of the present invention comprises the described compound of one or more other SARM administrations of associating.In some embodiments, method of the present invention comprises combined preparation, and described preparation comprises described compound and medicament mentioned above.In some embodiments, for example for the needs of tackling part patient subgroups to be treated or the needs of single patient, described combined preparation can change, described different needs may be owing to disease specific, described severity of disease, age, sex or body weight, and this can easily be determined by those skilled in the art.In some embodiments, method of the present invention comprises the personalized administrated method of the needs of handling single patient.In one embodiment, different needs are attributable to disease specific, described severity of disease, patient's holistic medicine state or described patient's age.In some embodiments, personalized medication is applying gene group data with sending of directed medical intervention better.In some embodiments, personalized administrated method is as the instrument of discovery and clinical trial product innovation of the present invention.In one embodiment, personalized medication comprises diagnostic tool useful on the applying clinical, and described instrument may help to determine the susceptibility of patient to disease specific or illness.In some embodiments, personalized medication is comprehensive method, and it utilizes the analysis of molecules of patient and healthy individual to instruct decision in the discovery of medicine and diagnosis and all stages of development; Be applied to more effectively provide accurate and high-quality health care by the prevention, diagnosis, treatment and the monitoring method that improve with the knowledge of this clinical practice.
In some embodiments, can be in the female appreciation cycle of animal or human's class, effectively to regulate the compound of the amount Medicine-feeding type (I) of fertilizability, perhaps in some embodiments, irregular or effectively synchronously or suppress the compound of amount Medicine-feeding type (I) of the breeding time of commercialization animal (for example fish, ox, sheep, pig, goat or chicken), laboratory animal (for example ape, chimpanzee, rat, mouse or cavy) or domestic animal (dog, cat, ferret, rabbit or horse) with the human menstrual cycle of effective control.In some embodiments, can be with the compound of the amount Medicine-feeding type (I) of effective minimizing menstruation, be used for the treatment of thus or prevent anaemia and dysmenorrhoea.In some embodiments, can be with the compound of the amount Medicine-feeding type (I) of effective prevention or treatment premenstrual tension syndrome, endometriosis, leiomyoma (hysteromyoma) and/or ovarian cysts.And for the individuality of suffering from or suffered from the past pelvic inflammatory disease (wherein the uterine tube cicatrization may take place), the compound that can use formula (I) is to reduce the probability that tubal pregnancy may take place.
In some embodiments, can be with the compound of the pregnant amount Medicine-feeding type (I) of effective prevention.In some embodiments, this administration can be before ovulation or before the sexual intercourse or after the ovulation or after the sexual intercourse.In some embodiments, this administration suppresses individual embryo implants, or suppresses individual ovulation in some embodiments.
In some embodiments, can be with the compound of the amount Medicine-feeding type (I) of effectively inducing female cervix maturation.Described cervix maturation can be L﹠D offspring's the preparation or the preparation of the dilatation and curettage of the uterus.In another embodiment, implementing this administration gives birth to from individuality with inducing embryo or fetus.
Any purposes that should be understood that any compound as herein described may be used to treat any disease described herein, obstacle or illness, and represents embodiment of the present invention.
Embodiment shown below is for the preferred embodiments of the invention more fully are described.But they in no case should be interpreted as limiting broad range of the present invention.
Embodiment
Embodiment 1
I
Compounds X III's is synthetic
2-substitutional crylic acid (compound 46) and 4-cyano group-3-5-trifluoromethylaniline reaction carry out epoxidation then.In the presence of salt of wormwood, make the epoxide open loop, produce compounds X III, as shown in Figure 1B with right-CN-phenol.
Embodiment 2
Compound V's is synthetic
Epoxidation is carried out in 4-cyano group-3-5-trifluoromethylaniline and propylene-2-SULPHURYL CHLORIDE (51) reaction, makes the epoxide open loop with p-CN-phenol then in the presence of salt of wormwood, produces compound V, as shown in Fig. 1 C.
Embodiment 3
Compounds X I's is synthetic
Make oxiranylmethyl radical t-butyl carbamate (54) open loop with p-CN-phenol, obtain compound 55, use the TFA deprotection then, obtain amino alcohol 56.In the electrophilic substitution reaction with compound 56 introducings and 4-fluoro-2-trifluoromethyl benzonitrile, form compound 58.Be oxidized to corresponding carbonyl derivative 59 with 58, be used for further addition reaction with 59, obtain compounds X I, it is as shown in Fig. 1 D.
Embodiment 4
Compounds X XXV's is synthetic
By initial compounds 3,6-two oxa-s-dicyclo [3.1.0] hexanes (60) preparation 4-methylene radical-tetrahydrofuran (THF)-3-alcohol (61) shows as Fig. 1 E.This compound is used for carrying out the reaction of Mitsunobu type with p-CN-phenol (50), forms compound 62.Use OsO 4Carry out dihydroxy, under the existence of TEMPO base (2,2,6,6-tetramethyl piperidine piperidyl oxygen), use NaClO then 4Carry out oxidation, form acid 64.Use thionyl chloride and 4-cyano group-3-5-trifluoromethylaniline to produce compounds X XI, as shown in Fig. 1 E by compound 64.
Embodiment 5
Compounds X XXVI's is synthetic
Prepare compound 62 as described in example 4 above, carry out epoxidation then, obtain compound 65, as shown in Fig. 1 F.Make the epoxide open loop with the 4-CN-3-5-trifluoromethylaniline, produce compounds X XXVI, as shown in Fig. 1 F.
Embodiment 6
Compounds X LVI's is synthetic
4-cyano group-3-5-trifluoromethylaniline and itaconic anhydride (66) reaction obtain intermediate 67.Further epoxidation also makes the epoxide open loop with right-CN-phenol, produces compounds X LVI, as shown in Fig. 1 G.
Embodiment 7
Synthetic (Fig. 2) of compounds X LIII
Make tetramethyleneimine-2-carboxylic acid (56) acidylate by schotten-Baumann reaction, obtain methacryloyl tetramethyleneimine-2-carboxylic acid (57), in the presence of N-bromo-succinimide, it is lactonized subsequently, obtain bromine lactone (58).Under refluxad, with 24%HBr solution with described bromine lactone (58) hydrolysis 1h, carry out aftertreatment subsequently and in ethyl acetate-hexanes mixtures recrystallization, obtain the 3-bromo-2-hydroxy-2-methyl propionic acid (59) [59: white solid (yield: 85%) Mp.108 ℃ [α] of high yield D 25=+10.5 (c=2.5,10MeOH) NMR ( 1H, 300MHz, DMSO): 1.35 (s, 3H, CH 3), 3.5 (s, 1H, CH), 3.6 (s, 1H, CH), 4.0 (br, 1H, OH) MS:205 (M+Na +) C 4H 7BrO 3Calculate: C, 26.25; H, 3.86 find: C, 26.28; H, 3.75].
Then, by be cooled to 0 ℃ under argon atmospher, hydroxyl and carboxyl with tribromoacetaldehyde protection compound 59 under agitation drip the vitriol oil.Solution deepening behind the 2h; Remove ice bath, reaction mixture at room temperature stirs and spends the night.Solution is with the ice dilution and use ethyl acetate extraction, and anhydrous sodium sulfate drying also concentrates, and obtains compound 60, and behind the recrystallization, the outward appearance of this compound is a white crystal from ethyl acetate-hexane.[60: white solid (yield: 89%) Mp.97 ℃ of NMR ( 1H, 300MHz, CDCl 3): 1.8 (s, 3H, CH 3), 3.7 (s, 2H, CH 2), 5.8 (s, 1H, CH) C 6H 6Br 4O 3Calculate: C, 16.17; H, 1.36; Find: C, 16.08; H, 1.25].
Compound 60 is dissolved in the mixture of 1: 1 2-propyl alcohol and 1M NaOH and at room temperature stirs.Behind the 3h, when detecting less than raw material by TLC, adding 4 '-fluoro thiophenol, reaction mixture stirs and spends the night.Then, reaction mixture is adjusted to pH 1, with ethyl acetate extraction and use anhydrous sodium sulfate drying with dense HCl.Concentrate organic layer, obtain oil.In hexane-ethyl acetate-acetate mixture, reaction mixture is carried out rapid column chromatography, in ethyl acetate-hexane, carry out recrystallization then, obtain colourless acicular crystal.By making this compound hydrolysis to remove protecting group, obtain the chirality hydroxy acid (55) shown in Fig. 2 [55: white solid (yield: 65%) M.p.54 ℃ with dense HCl acidified reaction mixture; [α] D 25=+24.85 (c=1.0, MeOH) NMR ( 1H, 300MHz, CDCl 3): 1.5 (s, 3H, CH 3), 3.2 (d, 1H, CH), 3.4 (d, H, CH), 7.0 (m, 2H, Ar, J=2.0Hz, 8.9Hz), 7.5 (m, 2H, Ar, J=2.0Hz, 8.9Hz) MS: no parent ion peak C 10H 11FO 3S calculates: C, 52.16; H, 4.82; Find: C, 52.05.59; H, 4.76].
By in 0 ℃ of adding thiophosgene and sodium bicarbonate in the chloroform medium, at room temperature stir then and spend the night, 4-nitro-3-5-trifluoromethylaniline is converted into corresponding isothiocyanate (66).Concentrated reaction mixture is extracted to it in ethyl acetate, drying, and evaporation is carried out purifying by the rapid column chromatography that uses hexane-ethyl acetate mixture, and obtaining outward appearance is 66 of yellow solid.Under agitation add hydroxy acid 55 and 4-nitro-3-trifluoromethyl isothiocyanate (66), trifluoroacetic acid silver acetonitrile solution and triethylamine, reaction mixture is heated to backflow, keeps 1h.By removing by filter silver sulfide, the pressure reducing and steaming solvent, the gained residuum washes with water, is extracted in the ethyl acetate, and is dry, filter also and concentrate.Separate by the rapid column chromatography that uses hexane-ethyl acetate mixture, desired product is rendered as yellow oil.Identify this compound Shi oxazolidinedione (65), as shown in Figure 2.[65: yellow oil (yield: 52%) [α] D 25=+39.7 (c=2.5,10 methyl alcohol) NMR ( 1H, 500MHz, DMSO): 1.8 (s, 3H, CH 3), 3.2 (s, 1H, 20CH), 3.3 (s, 1H, CH), 6.9 (m, 2H, Ar, J=2.0Hz, 8.9Hz), 7.2 (m, 2H, Ar, J=2.0Hz, 8.9Hz), 7.9 (m, 1H, Ar, J=2.1Hz, 9.0Hz), 8.0 (m, 1H, Ar, J=0.5Hz, 2.1Hz) 8.1 (and m, 1H, Ar, J=0.5Hz, 9.0Hz) NMR ( 13C, 500MHz, CDCl3): 22.8,43.4,86.7,117.0,117.3,124.4,124.5,124.6,125.0,126.8,129.3,134.2,134.3,135.3,164.9,172.8MS: no parent ion peak C 10H 11FO 3S calculates: C, 48.65; H, 2.72; N, 6.30 find: C, 48.59; H, 2.70; N, 6.31].
This product (65) ∏ acceptor/donor (R, R)-HPLC on the Whelk-O1 chiral column analyzes and show that ratio is 70: 30 two peaks, corresponding two enantiomers, the enantiomer excessive value is 40%.The generation that oxazolidinedione forms must be reset through perhydroxyl radical nucleophilic displacement silver sulfide and collaborative ring subsequently from the imines carbon, and this can be by intermediate structure (67a) and (67b) is confirmed; The machine-processed identical mechanism of setting up with people such as Shibuya.This paper considers, the good separation situation of the enantiomer that obtains in above-mentioned analysis mode chiral column can extend to corresponding preparative column, so that obtain the quantitative yield of described enantiomer, measure their absolute configuration thus with exciton coupling vibration circular dichroism (exciton coupled vibrationalcircular dichroism), and in order to Gauss's empirical Calculation method auxiliary measuring infrared spectra.This paper also considers, the Sauerstoffatom of heterocyclic system can be with the glycolylurea similar thing of amino replacement with the bicalutamide that obtains mapping, and described then analogue can interact for the hydrogen bonding with acceptor provide extra site.
Embodiment 8
Synthetic (Fig. 3) of compounds X LVIII
Prepare 4-bromo-2-trifluoromethyl benzonitrile (74) by diazotization by 4-cyano group-3-5-trifluoromethylaniline.Make 4-bromo-2-trifluoromethyl benzonitrile (74) and BuLi reaction generate the derivative (75) of Li.Make 3-bromobenzyl nitrile and BuLi reaction generate the derivative (77) of Li.With Li derivative (77) alkylation, obtain derivative (79) with (2-bromine oxethyl)-tertiary butyl dimethylsilane (78), 79 usefulness MeMgI are converted into methyl phenyl ketone (80).Subsequently, the Mitsunobu reaction also takes place with right-CN-phenol in deprotection, forms methyl phenyl ketone (82).Add Li derivative (75), dehydration obtains compounds X LVIII, as shown in Figure 3 then.
Embodiment 9
Synthetic (Fig. 4) of compounds X LIX
4-(2-hydroxyethyl)-pyridine-2-nitrile (83) is protected with tertiary butyl dimethylsilane, and be translated into corresponding methyl phenyl ketone (85) with MeMgI, deprotection prepares ether (87) then.Add Li derivative (75), dehydration obtains compounds X LIX, as shown in Figure 4 then.
Embodiment 10
Synthetic (Fig. 6) of compound L
By right-CN-phenol (50) preparation phosphorane (98), 98 generate derivative (100) with 3-acetylbenzene formaldehyde (99) in Wittig reaction by 4-chlorine HOMOVERATRONITRILE (97).Subsequently, add Li derivative (75) as described in example 8 above, dehydration obtains compound L, as shown in Figure 6 then.
Embodiment 11
Synthetic (Fig. 7) of compound L I
With tertiary butyl dimethylsilane protection 3-methylol benzonitrile (101), obtain compound (102), obtain corresponding methyl phenyl ketone (85) with MeMgI subsequently.Remove protecting group, further with right-CN-phenol reactant to obtain (105).Add Li derivative (75) (as prepared among the embodiment 8) in (105), dehydration obtains compound L I, as shown in Figure 7 then.
Embodiment 12
Synthetic (Fig. 5) of compound L II
With tertiary butyl dimethylsilane protection 5-bromo-2-hydroxy benzonitrile (88), obtain compound (89).Compound (89) and BuLi reaction obtain Li derivative (90), and it further by the alkylation of (2-bromine oxethyl)-tertiary butyl dimethylsilane, obtains (91).Compound (91) is reacted into corresponding methyl phenyl ketone (92) with MeMgI, and deprotection is also optionally protected phenolic group then, obtains derivative (94).Derivative (94) and right-CN-phenol reactant obtain compound (95), add Li derivative (75) and dehydration (as described in example 8 above) then, obtain compound (96).Deprotection obtains compound L II, as shown in Figure 5 subsequently.
Embodiment 13
General synthetic (Fig. 1 I) of compounds X XIV
Prepare 4-(4-arylsulfonyl-2,5-lupetazin-1-yl)-2-trifluoromethyl benzonitrile according to Fig. 1 I.In the DMSO-water mixture in the presence of salt of wormwood, with 2, the fluorine atom in the 5-lupetazin nucleophilic substitution 4-fluoro-2-trifluoromethyl benzonitrile.In the presence of triethylamine, by with the corresponding arylsulfonyl derivative of the prepared in reaction of aryl sulfonyl chloride.
Embodiment 14
Androgen receptor (AR) combines and the AR-SARM crystalline structure with SARM's
Method
Avidity is measured
Come the belly prostate gland of (family name) rat to obtain cytosol AR by Si Pula-Dao.The excision prostate gland also is immersed in (10mM Tris, 1.5m MEDTA disodium, 0.25M sucrose, 10mM Sodium orthomolybdate and 1mM PMSF) in the ice-cold homogenate buffer immediately.Prostate gland is shredded homogenate and centrifugal (Model L8-M, Beckman Instruments Inc) with scissors.Collection supernatant liquor (cytosol) also is stored under-80 ℃ up to use.At the compound of interest (10 that exists or do not exist concentration to increase -1NM-10 4NM) under the situation, in 4 ℃ down with saturation concentrations 3The Triamcinolone Acetonide of H-MIB (1nM) and 1 μ M is cultivated the AR cytosol 18h of equal portions (50 μ L).
By in nutrient solution, adding 1000nM MIB, measure 3The non-specific binding of H-MIB.Use the hydroxyapatite separation and combination with the free radioligand and measure bonded 3The concentration of H-MIB.Use non-linear regression to measure IC 50, promptly suppress 50% 3The concentration of the specificity bonded test compound of H-MIB.
Measure the avidity of compound of the present invention and be presented in the following table:
Figure A20078003470101811
Cotransfection is measured
Making CV-1 cell (green monkey kidney cell) improve to grow in the T175 tissue culture flasks on the Yi Geershi substratum (DMEM) at the Da Erbaikeshi that has replenished 10%FBS, 2mM glutamine and 1% Streptomycin sulphate and penicillin merges.Among the serum-free DMEM, with cell with 3 μ g CMVhAR expression vectors, 30 μ g male sex hormone dependent form luciferase reporter gene constructs (pMMTV-luc) and 30 μ g beta-galactosidase enzymes expression construct (pSV-beta-galactosidase enzymess; Promega, 5Madison is WI) through 30mLPlus reagent (Invitrogen) and 40mL LipofectAMINE (Invitrogen) transfection.After 4 hours, substratum is changed into the DMEM that replenishes 0.2%FBS and 2mM glutamine.After 12 hours, with cell transfer to 24 hole tissue culturing plate, after 6 hours, with the medicine of 0.1nM-1000nM or do not add medicine (contrast) and handle.After other 24 hours, cell is with cold PBS washed twice, cultivates collecting cell after 30 minutes by separate damping fluid (Promega) with the molten born of the same parents of the passivity of 100ML.
Equal portions (50ML) lysate is added to opaque 96 orifice plates, after injecting 50mL luciferase substrate (Promega) automatically, with MicroLumatPlus LB96V luminometer (BertholdTechnologies, Oak Ridge TN) uses the WinGlow software package to monitor the activity of luciferase.Lysate and 50mL beta-galactosidase enzymes mensuration damping fluid with equal portions (50mL) is added to 96 transparent orifice plates together in addition.After cultivating 2 hours under 37 ℃, read to measure absorption value in 420nm on the plate device at Dynex MRX.Make luciferase activity and betagalactosidase activity stdn, so that calculate the difference of cell quantity and/or transfection efficiency loss.
Clone, expression and purifying
Obtain AR-LBD (663-919) by total length AR expression construct (pCMVhAR) by carrying out pcr amplification, be inserted into then in the pGEX6P-1 plasmid vector (Amersham) with the primer that contains the flank restriction site.By inducing with 30 μ M IPTG, described AR LBD is glutathione-S-transferase (GST) fusion rotein in expressing 16 hours under 15 ℃ in e. coli bl21 DE3.Containing 150mM NaCl, 50mM Tris pH 8.0,5mM EDTA, 10% glycerine, 1mg/mL N,O-Diacetylmuramidase, 10U/mLDNA enzyme I, 10mM MgCl 2, 10mM DTT, 0.5%CHAPS, 100 μ M parts and 100 μ M PMSF damping fluid in, by three freeze-thaw cycle, with cytolysis.Cultivate 1h by supernatant liquor and glutathione agarose gel (Amersham) that ultracentrifugation obtains down at 4 ℃, and wash with 150mM NaCl, 50mM Tris pH 8.0,5mM EDTA, 10% glycerine, 10mM ATP, 10DM part, 0.1%n-octyl group-β-glucoside and 1mM DTT.
Under 4 ℃, containing the cutting GST-LBD fusion rotein that spends the night in the damping fluid of 150mM NaCl, 50mM Tris pH 7.0,10% glycerine, 0.1%n-octyl group-β-glucoside, 1mM DTT and 5U/mg protein PreScission proteolytic enzyme (Amersham) from the glutathione agarose gel, to discharge AR LBD.Supernatant liquor 3 times of dilutions in the hydroxyethyl piperazine ethanesulfonic acid of 10mM pH 7.2,10% glycerine, 10 μ M parts, 0.1%n-octyl group-β-glucoside, 1mM DTT are loaded on the HP SP cationic exchange coloum (Amersham) then.In identical dilution buffer liquid, use the NaCl gradient elution albumen of 50mM-500mM.Hold back in the thickener damping fluid changed at Millipore 10kD and contain 150mM Li 2SO 4, the damping fluid of the hydroxyethyl piperazine ethanesulfonic acid of 50mM pH 7.2,10% glycerine, 100 μ M parts, 0.1%n-octyl group-β-glucoside and 10mM DTT concentrates extremely protein greater than 4mg/mL.
Crystallization, collection data and structure determination
In one to two day, utilize hanging drop evaporation diffusion process in the Trisodium Citrate of 0.1M pH 7.5 hydroxyethyl piperazine ethanesulfonic acid and 0.5M-0.8M, to form AR LBD crystal.In liquid nitrogen, before the quick freezing, AR LBD crystal is transferred in the solution of being made up of hydroxyethyl piperazine ethanesulfonic acid, 0.7M Trisodium Citrate and 20% ethylene glycol of 0.1M pH 7.5.Use Rigaku RU300 rotating anode producer and R-axle IV++ imaging plate (Rigaku) to collect diffraction data, and handle (Molecular Structure Corporation) with Crystal Clear software.AR LBD-DHT mixture (PDB encode 1I37) is as using Crystallography﹠amp; NMR System (CNS) carries out the purified initial structure.In the first round refining after, electron density map makes the accurate match of part (fitting).Service routine O adds model construction thing and water molecules, uses the single temperature factor module of stiffener, torsion(al)angle simulated annealing and CNS to carry out the refining of more wheels.
The X ray research of SARM
To show that AR further analyzes in luciferase assay in conjunction with the SARM that is lower than 100nM, whether have the functional agonist activity of AR to determine them.Subsequently, make and have the most highly active SARM and AR acceptor cocrystallization and carry out X-ray analysis.
Embodiment 15
The functionally active of SARM
Ether shown in table 1 has been described connects the structure and the affinity of compound (bicalutamide analogue).All compounds all use the chirality synthetic method synthetic, comprise using the D-proline(Pro) as chiral auxiliary(reagent), and as United States Patent (USP) 6,995, in 284 disclosed ground, and this patent is incorporated herein by reference.Use ultimate analysis and spectral data, promptly 1H NMR, 13C NMR, MS and IRE determine the structure of synthetic compound.
Aspect more of the present invention, the design of these compounds fully understands the structural element that is accredited as the AR avidity that relates to the bicalutamide analogue, for example: (i) the aromaticity A of electron deficiency ring, (ii) at the R-of chiral centre configuration with (iii) at the electrophilic group of the contraposition of B ring.Be noted that importantly that in this quasi-molecule when replacing thioether or alkylsulfonyl to connect with ehter bond, the chirality indication of active compound becomes (S) from (R).Except these to the required constitutional features of high AR binding affinity, it is the key determinative of the functionally active of bicalutamide analogue that B ring replaces with the character that is connected basic X.
Table 1:
Numbering R1 R2 X R3 R4 R5 R6 R7 K i(nM)
Bicalutamide CN CF 3SO 2H H F H H 11 ± 2
R-20 NO 2 CF 3 SO 2 H H COCH3 H H 9.3±0.8
S-1 NO 2 CF 3 O H H F H H 6.1±0.19
S-2 NO 2 CF 3 O H H COCH3 H H 36.6±2.3
S-3 NO 2 CF 3 O H H COCH 2CH 3 H H 6.1±0.14
S-4 NO 2 CF 3 O H H NHCOCH3 H H 4.0±0.70
S-5 NO 2 CF 3 O H H CH 3 H H 34.8±3.5
S-6 NO 2 CF 3 O H H OCH3 H H 13.7±0.68
S-7 NO 2 CF 3 O H H NHCO 2C(CH 3)3 H H 336.0±71.1
S-9 NO 2 CF 3 O H H H H H 4.6±0.26
S-10 NO 2 CF 3 O F H F H H 3.4±0.34
S-11 NO 2 CF 3 O H F F H H 3.4±0.56
S-12 NO 2 CF 3 O F H F H H 3.2±0.30
S-13 NO 2 CF 3 O CH3 H F H H 6.0±0.70
S-14 NO 2 CF 3 O H Cl F H H 10.3±2.0
S-15 NO 2 CF 3 O H F Cl H H 4.9±0.3
S-16 NO 2 CF 3 O H Cl Cl H H 1.0±0.088
S-17 NO 2 CF 3 O F F F H H 11.3±1.1
S-18 NO 2 CF 3 O F H F H F 10.3±2.0
S-19 NO 2 CF 3 O F F H F H 9.1±0.6
S-20 NO 2 CF 3 O F F F F F 1.4±0.34
S-21 NO 2 CF 3 O H H Cl H H 8.6±1.2
S-22 NO 2 CF 3 O H H Br H H 12.6±1.8
S-23 NO 2 CF 3 O H H I H H 22.6±1.6
S-24 NO 2 CF 3 O H H NHCSNH 2 H H 10.2±1.4
S-25 NO 2 CF 3 O H H NHCSNHCH 3 H H 271.2±37.2
S-26 CN I O H H F H H 3.3±0.10
S-27 CN CF 3 O H H Cl H H 3.4±0.08
S-28 CN CF 3 O H H NHCOCH 3 H H 12.7±0.02
S-29 CN Cl O H H F H H 4.5±0.11
S-30 CN CF 3 O H H F H H 3.3±0.08
S-31 F CF 3 O H H F H H 32.6±0.10
S-32 Cl CF 3 O H H F H H 14.5±0.18
S-33 I CF 3 O H H F H H 15.6±0.19
S-34 Br CF 3 O H H Cl H H 52.0±0.13
S-35 Br CF 3 O H H Br H H 25.9±0.04
S-36 H CF 3 O H H F H H 62.0±0.05
In vitro study (Fig. 8) to the transcriptional activation of AR mediation shows, X connected to be become oxygen or B is encircled para-orientation by sulfone become acetamido by fluorine and all pure AR antagonist is converted into agonist, for example in compound S-5 and R-20.In the test, lead compound S-1 and S-4 are used as the AR agonist in vivo and demonstrate tissue selectivity (Fig. 9 A-9B) in vivo.S-1 and S-4 are partial agonist in prostate gland, but are full agonists in musculus levator ani, bone and hypophysis, and these are features that the ideal SARM is proposed.
Oral administration biaavailability and the security of S-4 are proved (data not shown), have proved conclusively the viewpoint that these compounds may effectively be treated hypoandrogenism disease or illness.Before verified, S-1 and S-4 are not the substrates of 5.This paper considers that the tissue selectivity of these parts is that the enzyme of DHT is expressed, testosterone is converted into to 5 in prostate gland rather than in the muscle because their agonist activities in prostate gland are not amplified by 5 fully.
The X-of all cpds of table 2 demonstration greatest treatment efficacy percentage ratio his-and-hers watches 1 and the dependency of Y-position.As described in example 13 above, use the rat abdomen cytosol, utilize competitive binding assay to measure the avidity of complete AR as the AR source.As described in example 13 above, use cotransfection to measure, detect the external functionally active of complete AR.Under the 10nM part, analyze treatment power (being transcriptional activation), activity is expressed as percentage ratio to the observed maximum transcriptional activation of 1nM Standone (DHT).
Table 2
Figure A20078003470101872
Embodiment 16
On-steroidal part bonded structural characterization
To a series of 4 "-fluorophenyl-2-hydroxy-2-methyl-N-(4 '-nitro-3 '-trifluoromethyl) propionanilide compound carries out conformational analysis, and these compounds are the heteroatoms difference of X position only.This analyzing and testing X position substituting group to the influence of compound conformation in the solution with exploitation conformation compound.With ligand solution (DMSO-d 6) the R-bicalutamide-W74L-LBD crystalline structure from resolving recently of NMR conformation and they (is called bicalutamide-W741L herein; C.E.Bohl, W.Gao, D.D.Miller, C.E.Bell, J.T.Dalton.Structural basis for antagonism and resistanceof bicalutamide in prostate cancer.Proc Natl Acad Sci U S A 2005,102 (17), making comparisons 6201-6.) in conjunction with conformation.Expected the bonding (NH-OH) of the intramolecularly hydrogen in connecting portion, this has observed in comformation in solution.Yet for some analyzed compounds, this intramolecularly NH hydrogen bond is shared for giving between OH and X position.The NH-X hydrogen bond causes the overall shape of described part in solution to obtain beyond thought bending, this bending with in the homology modeling process of AR, obtain hypothetical obviously different in conjunction with conformation.In the past, propionanilide there is not the hypothesis of hexa-atomic 5 cyclic n nitroso compound H-X hydrogen bonding conformations.(X=S is Y=F) with partial agonist S-23 (X=O for agonist S-4 (X=O, Y=N-ethanoyl) and X-2; Y=I) and S-1 (X=O; Y=F) NH that clearly shows phenyl ring in this solution adds-OH conformation (Figure 10) to-X, still, and for this serial antagonist X-3 (X=SO 2, Y=F) and X-4 (X=NH, Y=F) and X-5 (X=CH 2, Y=F) do not observe this conformation.This shows, described part takes the ability of this conformation to activate very important to AR, this point by with the conformation of on-steroidal part relatively obtain conclusive evidence, the conformation of described on-steroidal part is observed in the x-ray crystal structure of the R-bicalutamide-W741L-LBD that resolves subsequently (AR mutant, wherein bicalutamide is as agonist).
Table 3 provides the result that intramolecular hydrogen bond is analyzed in the solution of all cpds of being identified in the table 1.As using in the table 3, the definition of hydrogen bond is＜3.1
Figure A20078003470101881
Interatomic distance, the operational analysis in SYBYL 6.8 of this distance-distance order records.
Comformation in solution uses the NOESY spectrum to measure.NH-OH refers to the interatomic distance between the oxygen of the proton of connecting portion acid amides and connecting portion hydroxyl, and NH-X refers to the interatomic distance between the atom of the proton of connecting portion acid amides and connecting portion X position.S-1 external as partial agonist, S-4 and X-2 external be agonist, X-3, X-4 and X-5 external be antagonist.
Table 3:
Figure A20078003470101882
Make up the locus specificity mutant of AR, detect DHT and three kinds of abilities of transcribing (Figure 11) that the on-steroidal parts are Sch 16423 (HF), bicalutamide and S-4 stimulation AR mediation.In this mutant, bicalutamide shows as agonist and stimulates the transcriptional activation of AR mediation, shows that the W741L mutant AR-LBD in conjunction with bicalutamide takes to be similar to the activity conformation of using in conjunction with the observed conformation of wild-type AR of agonist.Consider the difficulty of purifying, prove useful in conjunction with the W741L mutant of bicalutamide with in conjunction with the agonist conformation of the T877A mutant of Sch 16423 in conjunction with the wild-type LBD of antagonist.This paper considers that these mutant mixtures can be taked compacter conformation, can promote dissociating of in the purifying of LBD and crystallisation process chaperone protein like this, and for we provide understanding first to on-steroidal AR part binding mechanism.
Use is similar at first the described method of scientist of resolving with steroid part bonded AR-LBD crystalline structure, will be in conjunction with the wild-type LBD of R1881 and DHT, DHT-5 with in conjunction with the W741L LBD purifying and the crystallization of bicalutamide.And, use the higher bicalutamide R-isomer of avidity.In intestinal bacteria, GST-LBD and part co expression.Behind affinity chromatography and crack fusion protein, the high pI (iso-electric point) of LBD makes impurity albumen and chaperone protein remove by the neutral pH cation-exchange chromatography.
These two kinds of mixtures are all taked and the very similar whole conformation of the LBD of association class sterol (Figure 12 A).Indicate as NMR institute by comformation in solution; bicalutamide forms intramolecular hydrogen bond (Figure 12 B) between alkylsulfonyl oxygen and amine proton; this model (Figure 10) with computer forecast is different; indicating this is to be different from the conformation that ether connects analogue, and shows that NMR research to the ligand solution conformation may be used to predict the part conformation when combining with LBD.This knot resembles explanation, and these sport the on-steroidal part provides more space with embedding (fit into) LBD, and forms by the observed agonist conformation of wild-type DHT mixture.
The position class of most of LBD residues in wild-type DHT mixture is similar to the on-steroidal mixture, although the intensity of variation of ligand structure surprising (Figure 13 A).Sch 16423 (HF) and R-bicalutamide have similar A ring and amido link structure, and this makes steroid plane overlapping fully (Figure 13 B).Observe hydrogen bond between the nitro/cyano group of R752 and A ring, this has simulated the 3-ketone group among the DHT, and also observes hydrogen bond between L704 and N705 and hydroxyl, and this has simulated 17 β among the DHT-OH.Yet different with DHT is not observe hydrogen bond between on-steroidal part and T877 side chain.
There is very big difference (Figure 13 B) position of also observing residue in the sulfone connection base and the B ring zone of R-bicalutamide, the folding top of leaving the steroid plane and pointing to pocket (pocket), this zone may take the W741 indole ring space of (not existing) in mutant.In T877A-HF and WT-DHT mixture, the position of W741 indole ring is also distinguished very big.In the DHT mixture, the Trp741 side chain contacts with part, and in the T877A-HF mixture, this indole ring is farther apart from binding pocket (bindingpocket).As if M745 can explain these differences by the 19-methyl displacement of DHT.See also that in Figure 13 B compare with T877A-HF with wild-type DHT, R-bicalutamide alkylsulfonyl causes the displacement of spiral 12 residue M895.Yet this M895 side chain is accommodated in the position of W741 indole ring of T877A-HF mixture.In wild-type LBD, W741 and M895 side chain all may have the interaction that disadvantageous prevention agonist conformation forms with bicalutamide.On the other hand, the fluorine in the contraposition of the B of R-bicalutamide ring is in the hydrophilic region combination of AR, and described zone also provides the chance that forms hydrogen bond.This zone of AR reversing between spiral 4 and 5 located and is very approaching with the H874 imidazoles.The compound proof that is replaced by acetamido S-4, isothiocyanate, cyano group or nitro in this position has the avidity of improvement to AR, shows that they may form favourable hydrogen bond in this zone.
Embodiment 17
Constitutional features in conjunction with the AR LBD of agonist and antagonist
Dissociating of HSP is one of initial procedure of causing of the AR LBD conformational change by agonist induction.In mammalian cell, the HSP mixture mainly comprises HSP90, HSP70, p60 and p23.HSP90 directly and receptors bind become homodimer, and other protein mainly combines with this mixture by HSP90.HSP90 binding site among the AR LBD is not also characterized well.The residue 720-774 that comprises ring 3-4, H4 and H5 just in time forms most AF2 hydrophobicity groove (Figure 14 A-14B), and they are accredited as the zone in conjunction with HSP90 that may be responsible for using brachymemma.
Importantly, this paper considers that the alpha-helix of the unusual HSP90 that is exposed to solvent and the H12 of nuclear receptor family are very similar, and may replace H12 on these acceptors with the combination of promotion part.This viewpoint especially may be relevant with AR because the function of AR compare with other nuclear receptor as if having important different.The IP of radiolabeled AR and sucrose gradient centrifugation analysis show, agonist R1881 (rather than antagonist Sch 16423 and bicalutamide) induces HSP90 to dissociate, and the existence of this explanation chaperone protein mixture rather than the MAEII die body of H12 stop near the AF2 district.Therefore, dissociating of HSP90 seems directly relevant with the activity of AR part.
Though Sch 16423 is as the antagonist of wild-type AR, it plays the agonist effect to T877A AR mutant.Its agonist activity to the AR of sudden change is directly relevant with dissociating of HSP90.These are different fully with ER, and wherein ER agonist and antagonist all start dissociating of HSP.Compare with the situation of ER, dissociating of HSP90 seemingly can influence the more The key factor of the conformation of acceptor to AR LBD.This explanation AR antagonistic activity may relate to another kind of mechanism.
The limited proteolysis analysis revealed of different AR mixture, the part inductive of AR activates the twice successive conformational change that needs LBD.The AR agonist, promptly T, DHT and R1881 have stablized the 29-KD fragment of AR and have resisted restricted tryptic digestion, and androgen antagonist, promptly cyproterone acetate, Sch 16423, Nilutamide and bicalutamide are stablized the 35-KD fragment.29-KDa and 35-KDa fragment all contain complete LBD (amino acid 671-919), and the 35-KDa fragment extends into hinge area (amino acid 621-671).The 35-KDa fragment also participates in agonist bonded initial step, still its instability under long digestion.
This time-dependent manner conformational change is postponed by the adding of molybdate, and this dissociating of HSP of explanation may cause hinge area to be exposed to tryptic digestion.Therefore, propose, agonist is in conjunction with the conformational change first time that starts AR, and this triggers dissociating of HSP, begins conformational change for the second time then.Yet although antagonist can start conformational change for the first time, it can not promote dissociating of HSP, and this has stablized LBD and hinge area and has protected hinge area not to be subjected to further tryptic digestion.
Embodiment 18
SARM is carried out the completely new approach of medicinal design (SBDD) based on structure
Design aspect the agonist in the conformation that combines, make us know the binding pattern of compound provided herein clearly with antagonist bicalutamide bonded AR mutant W741L (bicW741L) based on agonist and AR.This also provides principle for the binding pattern feature of distinguishing agonist and antagonist.The crystalline structure of the wild-type AR in conjunction with agonist S-1 (S1-wild-type) that resolves has been proved conclusively observed binding pattern in the W741L mutant recently.1.8
Figure A20078003470101911
Sharpness under, these structures are all resolved, and these structures have proved novel binding pattern, this pattern fundamentally be different from before eutectic structure occurs, propose, by the indicated pattern of homology model.
Opposite with above-mentioned eutectic, homology model has unique cavity that is not occupied along the α-mask of (docked) steroid that is docked, and described hole is greatly to the B ring that enough can hold propionanilide.
Confirm brand-new SBDD model
The empirical analysis of these AR structural modelss being carried out by the analysis of Spearman relation conefficient provides the statistics means of ability of the rank order of each model prediction part avidity.For example brand-new design or virtual screening should be along which when the guidance of machine simulation (in silico) is carried out as calculated to estimate whether this model can be used in a preferential order determining based on the method for molecular docking when using, and this hierarchal order statistic is suitable.The Spearman that will be used for following AR model for the AR part database that comparative molecular field analysis (CoMFA) model is edited analyzes: CoMFA, in conjunction with the wild-type crystal (abbreviating the S1-wild-type as) of S-1, in conjunction with the W741L crystal (abbreviating bicalutamide c-W741L as) and the homology model of bicalutamide.CoMFA (C.E.Bohl, C.Chang, M.L.Mohler, J.Chen, D.D.Miller, P.W.Swaan, J.T.Dalton.A ligand-based approach to identifyquantitative structure-activity relationships for the androgen receptor.J MedChem 2004,47 (15), 3765-76.), S1-wild-type (C.E.Bohl, D.D.Miller, J.Chen, C.E.Bell, J.T.Dalton.Structural basis for accommodation of nonsteroidalligands in the androgen receptor.J Biol Chem 2005,280 (45), 37747-54.), bicalutamide-W741L (C.E.Bohl, W.Gao, D.D.Miller, C.E.Bell, J.T.Dalton.Structural basis for antagonism and resistance of bicalutamide in prostatecancer.Proc Natl Acad Sci U S A 2005,102 (17), 6201-6.) and G1 homology model ((C.A.Marhefka, B.M.Moore, 2nd, T.C.Bishop, L.Kirkovsky, A.Mukherjee, J.T.Dalton, D.D.Miller.Homology modeling using multiple moleculardynamics simulations and docking studies of the human androgen receptorligand binding domain bound to testosterone and nonsteroidal ligands.J MedChem 2001,44 (11), R 1729-40.) sValue is respectively 0.93,0.55,0.29 and-0.28, this explanation, and the significant predictor of S1-wild-type model and bicalutamide-limited predictor of W741L model show to compare with the former medicinal design model based on structure and make progress.Therefore, can predict that these crystalline structure can improve the ability of determining by the priority ranking of the guidance of computer simulation, promote medicinal design thus.
Embodiment 19
AR part bonded calculates the affirmation of prediction
Check to twisting strain parameter among the embodiment 16 and interaction of hydrogen bond shows that the arylprop acid amides derivative compound of compounds X VII takes to be similar to the conformation of compounds X LII.Hydroxyl α navigates to carbonyl by this way, the interaction of hydrogen bond of the l-asparagine 705 of its participation and acceptor.The main chain oxygen of this amino acid and leucine 704 forms weak hydrogen bond.The calculating prediction of being done is with consistent in conjunction with measuring the result who draws.Yet, in order to set up the conformation that above-mentioned interaction and molecule are taked convincingly, set up suitable molecular model, this model does not have free hydroxyl and amide proton, and the most important thing is that this model is confined to be similar to the structure of compounds X LII on conformation.Therefore, amide nitrogen and hydroxyl oxygen link by the carbonyl functional group, and this forms as the De oxazolidinedione derivant structure of describing among the compounds X XXIX.Implementing the stereoselectivity of the synthetic and Zhe Xie oxazolidinedione derivative of arylprop acid amides derived compounds synthesizes.
Embodiment 20
Compound L IV's is synthetic
By compound L III synthetic compound LIV, first group of compound being considered is by Simmons-Smith reaction synthetic cyclopropane series, shown in following route.
Figure A20078003470101931
Embodiment 21
Compounds X VI's is synthetic
Figure A20078003470101941
According to above-mentioned route synthetic compound XVI.According to US 06995284 synthetic R-3, this patent is incorporated herein by reference.Obtain XVI, be yellow oil: the quality 415.08 that calculates, [M-H] 414.0; 1H NMR (CDCl 3) 9.13 (bs, 1H, NH), 7.96 (d, J=9.0Hz, 2H, ArH), 7.88 (dd, J=9.0,2.1Hz, 1H, ArH), 7.43 (dd, J=7.6,1.5Hz, 1H, ArH), 7.11 (m, 1H, ArH), 6.72 (m, 2H, ArH), 4.15 (bs, 3H, OH﹠amp; NH2), 3.59 (d, J=14.1Hz, 1H, CH2), 3.02 (d, J=14.1Hz, 1H, CH2), 1.56 (s, 3H, CH3).
Embodiment 22
Compounds X L's is synthetic
As describing ground synthetic compound XL among Fig. 1 J.Add thiocarbanil in the L-L-Ala sodium salt in ethanol, warm 30 minutes.Boil off solvent, and in the oily residuum, add dense HCl.Collect the white solid that forms, in water, wash, obtain compound 2.Add diacetyl oxide, obtain compound 3, in the presence of hexamethyldisilazane sylvite, add 1-bromo-4-brooethyl benzene, obtain compounds X L.
Compound 2 1H NMR (CDCl 3): 7.65,7.63,7.61,7.38,7.35,7.25,4.40,1.62
Compound 3 1H NMR (CDCl 3): 7.59,7.57,7.56,7.39,7.33,4.92,2.90,1.74
Compounds X L's 1H NMR (CDCl 3): 7.53,7.52,7.51,7.50,7.49,7.40,7.39,7.37,7.34,4,38,1.67,1.66; The fusing point of compounds X L: 99 ℃.
Embodiment 23
Compounds X LI's is synthetic
As describing ground synthetic compound XLI among Fig. 1 K.Add 4-isothiocyano-1-nitro-2-trifluoromethylbenzene, warm 30 minutes in the L-L-Ala sodium salt in ethanol.Boil off solvent and in the oily residuum, add dense HCl.Collect the white solid that forms, in water, wash, obtain compound 2.Add diacetyl oxide, obtain compound 3, in the presence of hexamethyldisilazane potassium, add 1-bromo-4-brooethyl benzene, obtain compounds X LI.
Compound 3 1H NMR (CDCl 3): 10.80,8.35,8.18,7.99,4.49,1.43.
Compounds X LI's 1H NMR (CDCl 3): 7.97,7.47,7.43,7.42,7.19,7.15,6.97,6.92,3.93,3.15,2.88,1.98.
Though this paper has illustrated and described some feature of the present invention, those of ordinary skill in the art can draw many modifications, replacement, change and equivalents now.Therefore, should be appreciated that appending claims is intended to cover all and drops on the interior this modifications and variations of true spirit scope of the present invention.

Claims (144)

1. compound, its structure by formula I is represented:
Wherein
X is C or N; W is C or N;
X 1Be N, NH, N (C 1-4Alkyl), NAc, NCOOH or key; Perhaps X 1And X 3With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 1And X 5With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist;
P is H or formula II:
Figure A2007800347010002C2
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key; Perhaps X 2And R 3With X 2The X that is connected 1Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 2And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist;
X 3Be C 1-4Alkylidene group, NH, N, CH (OH), key; Perhaps X 1And X 3With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring; Perhaps X 3And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 3And X 4Form two keys together or form the first ring of saturated or unsaturated, replacement or unsubstituted 3-6 together;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key; Perhaps X 4And X 5With X 4And X 5The X that is connected 3Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 3And X 4Form two keys together or form the first ring of saturated or unsaturated, replacement or unsubstituted 3-6 together;
X 5Be carbon or X 5And X 1With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 5And X 2Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 5And X 3Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring, and A does not exist; Perhaps X 5And X 4With X 5And X 4The X that is connected 3Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring, and A does not exist;
A does not exist, or H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2Perhaps A and R form the represented two keys of formula III:
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, halogenide, CF 3, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, NH 2, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN, NO 2Perhaps R 3And X 2With R 3Phenyl ring that is connected and X 2The X that is connected 1Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring;
R ' is NH 2, OH or CH 3
R 4And R 5Be H, CH independently 3, halogenide, OH, C 1-4Alkyl, C 1-6Cycloalkyl, halo (C 1-4Alkyl), phenyl, aryl, C 4-8Heterocyclylalkyl or hydroxyl (C 1-4Alkyl);
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is that OH and A are alkyl or haloalkyl, X so 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], N[CH 2CH 2N (CH 3) 2], P (O) (C 1-4Alkyl) or N (O) [CH 2CH 2N (CH 3) 2];
Perhaps
If P is formula II, X is C, X 1Be NH, X 2Be C (O), X 3Be CH 2, R is OH or OAlk and X 4Be O, S, NH, S, SO, SO 2Or alkylidene group, A is CN, CH so 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Perhaps
If P is a phenyl, X is C, X 1Be NH, X 2Be C (O), R is that OH and A are COOH, X 3Be key, X 4Be CH 2, R 1, R 2Be H, Q is not H so;
Perhaps
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so;
Perhaps
If P is H, X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2And X 4Be key or CH 2, R 1And R 2Be H, Q is not H or halogen so;
Perhaps
If P is formula II, R 3Be H, X and W are C, X 1And X 5With X 1And X 5The X that is connected 2Xing Cheng oxazolidinedione together, R is an alkyl, X 3Be CH 2And X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
2. the compound of claim 1, it is represented by following structure:
Figure A2007800347010005C1
3. the compound of claim 1, wherein said compound is represented by the structure of formula IV:
Figure A2007800347010005C2
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
4. the compound of claim 3, it is represented by following structure:
Figure A2007800347010006C1
5. the compound of claim 2, wherein said compound is represented by the structure of formula V:
Figure A2007800347010006C2
6. the compound of claim 5, it is represented by following structure:
Figure A2007800347010007C1
7. the compound of claim 2, wherein said compound is represented by the structure of formula VI:
Figure A2007800347010007C2
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
8. the compound of claim 7, it is represented by following structure:
Figure A2007800347010008C1
9. the compound of claim 7, wherein said compound is represented by the structure of formula VII:
Figure A2007800347010008C2
10. the compound of claim 9, it is represented by following structure:
Figure A2007800347010008C3
11. the compound of claim 9, wherein said compound is represented by the structure of formula X:
Figure A2007800347010009C1
12. the compound of claim 11, it is represented by following structure:
Figure A2007800347010009C2
13. the compound of claim 7, wherein said compound is represented by the structure of formula IX:
Figure A2007800347010009C3
14. the compound of claim 13, it is represented by following structure:
Figure A2007800347010009C4
15. the compound of claim 7, wherein said compound is represented by the structure of formula X:
Figure A2007800347010010C1
16. the compound of claim 7, wherein said compound is represented by the structure of formula X:
17. the compound of claim 16, it is represented by following structure:
Figure A2007800347010010C3
18. the compound of claim 15, wherein A is CH 2OH.
19. the compound of claim 17, wherein A is CH 2OMe.
20. the compound of claim 17, wherein A is CF 3
21. the compound of claim 17, wherein A is CH 3
22. the compound of claim 17, wherein A is CN.
23. the compound of claim 1, wherein said compound is represented by the structure of formula XII:
Figure A2007800347010011C1
Wherein
X is C or N; W is C or N;
X 4Be O, S, SO, S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
24. the compound of claim 23, wherein X 4Be O.
25. the compound of claim 24, wherein A is CH 2OH.
26. the compound of claim 24, wherein A is CN.
27. the compound of claim 23, wherein Q is CN, R 1And R 2Be H.
28. the compound of claim 23, wherein Q is CN, and Z is CN, and Y is CF 3, and R 1, R 2And R 3Be H.
29. the compound of claim 23, it is represented by following structure:
Figure A2007800347010012C1
30. the compound of claim 23, wherein said compound is represented by the structure of formula XIII:
Figure A2007800347010012C2
31. the compound of claim 1, wherein said compound is represented by the structure of formula XVII:
Figure A2007800347010012C3
Wherein
X 4Be S (O) [=CHCH 2N (CH 3) 2], C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2];
Q is H, CN, OH, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br; And
Y is H, C 1-4Alkyl, CF 3, CN, NO 2, F, Cl, I or Br.
32. the compound of claim 31, wherein Q is F.
33. the compound of claim 31, wherein Q is CN.
34. the compound of claim 31, wherein Z is that CN and Y are CF 3
35. the compound of claim 31, wherein Q is CN, and Z is that CN and Y are CF 3
36. the compound of claim 1, wherein said compound is represented by the structure of formula XIX:
Figure A2007800347010013C1
Wherein
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 3Be C 1-4Alkylidene group, NH, N, CH (OH) or key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
Wherein
If X is C, X 1Be NH, X 2Be C (O), R is OH, and A is an alkyl, X 3Be key or CH 2, and X 4Be key or CH 2, R 1And R 2Be H, Q is not H or halogen so.
37. the compound of claim 36, wherein X 2Be CH 2
38. the compound of claim 36, wherein X 2Be C (O).
39. the compound of claim 36, wherein X 3Be CH 2
40. the compound of claim 36, wherein X 4Be O.
41. the compound of claim 36, it is represented by following structure:
Figure A2007800347010015C1
42. the compound of claim 1, wherein P is formula II, and X 2And X 3With X 1Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring.
43. the compound of claim 42, wherein said saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetramethyleneimine, pyrroles, morpholine, piperidin-4-one-or piperidines.
44. the compound of claim 42, wherein said compound is represented by the structure of formula XX:
Figure A2007800347010015C2
Wherein
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
A is H, OH, SH, NH 2, C 1-4Alkyl, CHF 2, CH 2F, CF 3, CN, CH 2OH, CH 2O (C 1-4Alkyl), CH 2O (C 1-4Acyl group), CH 2CN, CH 2N 3, CH 2NCS, CHO, C (O) O (C 1-4Alkyl), CONHR ', C (O) N (R ') 2, C (O) O (C 1-4Alkyl), C (O) R ', CH 2CF 3, CF 2CF 3, CH 2OR ' CH 2C (O) CH=CH 2Or C (O) CH=CH 2
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or B r;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or B r;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
45. the compound of claim 44, wherein A is CH 3
46. the compound of claim 44, wherein X 4Be O.
47. the compound of claim 44, wherein Q is CN.
48. the compound of claim 44, wherein Z is that CN and Y are CF 3
49. the compound of claim 44, wherein Z is CN, and Q is that CN and Y are CF 3
50. the compound of claim 44, wherein A is CH 3, X 4Be O, Z is CN, and Q is CN, R 1And R 2Be H, and Y is CF 3
51. the compound of claim 44, it is represented by following structure:
Figure A2007800347010016C1
52. the compound of claim 42, wherein said compound is represented by the structure of formula XXI:
Figure A2007800347010017C1
53. the compound of claim 52, wherein A is CH 3
54. the compound of claim 52, wherein X 4Be O.
55. the compound of claim 52, wherein Q is CN.
56. the compound of claim 52, wherein Z is that CN and Y are CF 3
57. the compound of claim 52, wherein A is CH 3, X 4Be O, Z is CN, and Q is CN, R 1And R 2Be H, and Y is CF 3
58. the compound of claim 52, it is represented by following structure:
Figure A2007800347010017C2
59. the compound of claim 42, wherein said compound is represented by the structure of formula XXII:
Figure A2007800347010017C3
Wherein A, Z, Y, X 4, Q, R 1And R 2Described in XX, R 7Be H or oxo, and R 8Be H or=CH 2
60. the compound of claim 58, wherein A is CH 3
61. the compound of claim 58, wherein X 4Be O.
62. the compound of claim 58, wherein R 7And R 8Be H.
63. the compound of claim 58, wherein R 7Be=CH 2And R 8It is oxo.
64. the compound of claim 58, wherein Q is CN.
65. the compound of claim 58, wherein Z is that CN and Y are CF 3
66. the compound of claim 58, wherein A is CH 3, X 4Be O, Z is CN, and Q is CN, R 1And R 2Be H, and Y is CF 3
67. the compound of claim 58, it is represented by following structure:
Figure A2007800347010018C1
68. the compound of claim 1, wherein P is formula II, and X 1And X 3With X 1And X 3The X that is connected 2And X 5Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring.
69. the compound of claim 68, wherein said saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be piperazine, piperazine-2,6-diketone, piperidines, tetramethyleneimine, pimelinketone, hexanaphthene, tetrahydrobenzene, cyclopentanone, pentamethylene, cyclopentenes, succinimide, oxazolidine, oxazolidinedione Huo oxazolidone.
70. the compound of claim 69, wherein said compound is represented by the structure of formula XXIII:
Figure A2007800347010019C1
X is C or N; W is C or N;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
71. the compound of claim 70, wherein X 4Be O.
72. the compound of claim 70, wherein Q is CN.
73. the compound of claim 70, wherein Z is that CN and Y are CF 3
74. the compound of claim 70, wherein X 4Be O, Z is CN, and Q is CN, R 1, R 2And R 3Be that H and Y are CF 3
75. the compound of claim 68, wherein said compound is represented by the structure of formula XXXIII:
Figure A2007800347010020C1
76. the compound of claim 75, wherein X 4Be O.
77. the compound of claim 75, wherein Q is CN.
78. the compound of claim 75, wherein Z is that CN and Y are CF 3
79. the compound of claim 75, wherein X 4Be O, Z is CN, and Q is CN, R 1, R 2And R 3Be that H and Y are CF 3
80. the compound of claim 1, wherein P is formula II, X 3And X 5Form saturated or unsaturated, replacement or unsubstituted 5-or 6-unit ring.
81. the compound of claim 80, wherein said saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetrahydrofuran (THF), tetramethyleneimine, piperidines, pimelinketone, hexanaphthene, tetrahydrobenzene, cyclonene, cyclopentanone, cyclopentenone, pentamethylene, cyclopentenes, succinimide, oxazolidine, oxazolidinedione, oxazolidone.
82. the compound of claim 80, wherein said compound is represented by the structure of formula XXXIV:
Figure A2007800347010021C1
X is C or N; W is C or N;
X 2Be C 1-4Alkylidene group, SO 2, C (O), CH-[CH 2-(C 4-8Ring)] CH (C, 1-4Alkyl), CH (NH 2), CH (OH), CH (C 1-4Haloalkyl), key;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, NO 2, CF 3, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
83. the compound of claim 82, wherein X 4Be O.
84. the compound of claim 82, wherein Q is CN.
85. the compound of claim 92, wherein X 2Be CH 2
86. the compound of claim 82, wherein X 2Be C (O).
87. the compound of claim 82, wherein Z is that CN and Y are CF 3
88. the compound of claim 82, wherein said compound is represented by the structure of formula XXXV:
Figure A2007800347010022C1
89. the compound of claim 82, wherein said compound is represented by the structure of formula XXXVI:
Figure A2007800347010022C2
90. the compound of claim 80, wherein said compound is represented by the structure of formula XXXVII:
Figure A2007800347010022C3
91. the compound of claim 90, wherein X 2Be CH 2
92. the compound of claim 90, wherein X 2Be C (O).
93. the compound of claim 90, wherein X 4Be O.
94. the compound of claim 90, wherein Q is CN.
95. the compound of claim 90, wherein Z is that CN and Y are CF 3
96. the compound of claim 80, wherein said compound is represented by the structure of formula XXXVIII:
97. the compound of claim 96, wherein X 2Be CH 2
98. the compound of claim 96, wherein X 2Be C (O).
99. the compound of claim 96, wherein X 4Be O.
100. the compound of claim 96, wherein Q is CN.
101. the compound of claim 96, wherein Z is that CN and Y are CF 3
102. the compound of claim 1, wherein P is formula II, and X 1And X 5With X 1And X 5The X that is connected 2Form saturated or unsaturated, replacement together or unsubstituted 5-or 6-unit ring;
Wherein
If P is formula II, X is C, X 3Be CH 2, X 4Be O or NH, R 1, R 2And R 3Be H, and X 5And X 1Form 5 Yuan Huan oxazolidine-2-ketone, Q is not halogen or H so; Perhaps
If P is formula II, R 3Be H, X and W are C, X 1And X 5With X 1And X 5The X that is connected 2Xing Cheng oxazolidinedione together, R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
103. the compound of claim 102, wherein said saturated or unsaturated, replace or unsubstituted 5-or 6-unit ring be tetramethyleneimine, piperidines, morpholine, succinimide, oxazolidine, oxazolidinedione, oxazolidone.
104. the compound of claim 102, wherein said compound is represented by the structure of formula XXXIX:
Figure A2007800347010024C1
Wherein:
X is C or N; W is C or N;
G is O, NH, NC 1-4Alkyl, NC 1-4Acyl group, S, CHC 1-4Alkyl, CHC 1-4Acyl group, C (C 1-4Acyl group) 2, C (C 1-4Alkyl) 2Or (CH 2) n, wherein n is 1-3;
T is S or O;
X 4Be O, S, SO, C (O), S (O) [=CHCH 2N (CH 3) 2], SO 2, NH, NHR ', NO, C 1-4Alkylidene group, C (OH) [CH 2CH 2N (CH 3) 2], C[=CHCH 2N (CH 3) 2], PO (C 1-4Alkyl), N[CH 2CH 2N (CH 3) 2], NO[CH 2CH 2N (CH 3) 2] or key;
Z is H, CN, NO 2, NHC (O) CH 3, C 1-4Alkyl, F, Cl, I or Br;
Y is H, C 1-4Alkyl, CF 3, NO 2, CN, F, Cl, I or Br;
Q is H, CN, OH, CF 3, NO 2, halogenide, C 2-6Thiazolinyl, C 2-6Alkynyl, C (O) CH 2NH 2, C (O) NH (C 1-4Alkyl), C (O) N (C 1-4Alkyl) 2, C (O) NH 2, NH (C 1-4Alkyl), NHC (O) NH (C 1-4Alkyl), CH 2C (O) NH 2, NHC (O) NH 2, NHCO (C 1-4Alkyl), NHSO 2(C 1-4Alkyl), O-[CH 2CH 2CH (CH 3) 2], O-[CH 2CH 2(C 4-8Cycloalkyl)], O-[CH 2CH 2(C 4-8Or O-[CH Heterocyclylalkyl)] 2CH 2N (CH 3) 2];
R is H, OH, C 1-4Alkyl, CF 3, CH 2OH, O (C 1-4Alkyl) or O (C 1-4Acyl group);
R 1Be H, OH, F, Cl, Br or I;
R 2Be H, by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, C 1-4Alkyl, halogenide, CN or NO 2
R ' is NH 2, OH or CH 3And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide;
If R wherein 3Be H, X and W are C, and G is O, and T is O, and R is an alkyl, X 3Be CH 2, and X 4Be O, NH, S, SO 2Or CH 2, Q is not a halogenide so.
105. the compound of claim 104, wherein said compound is represented by the structure of formula XLV:
Figure A2007800347010025C1
X wherein 4As above about as described in the compounds X XXIV.
106. the compound of claim 105, wherein X 4Be O.
107. the compound of claim 102, wherein said compound is represented by the structure of formula XLII:
Figure A2007800347010025C2
Wherein:
X, X 4, R, R 1, R 2, R 3, Z, Y and Q as above about as described in the compounds X XXIV;
Wherein
If X is C, X 4Be O, NH or S, R 1, R 2And R 3Be that H and R are H, Q is not halogen, H or CN so.
108. the compound of claim 1, wherein said compound is represented by the structure of formula XLVII:
Figure A2007800347010026C1
Wherein
X is N or CH;
Z is H, CN, NO 2, NHC (O) CH 3, CH 3, F, Cl, I or Br;
Y is H, CH 3, CF 3, CN, F, Cl, I or Br;
Q is H, O-(CH 2) 2CH (CH 3) 2Or O-(CH 2) 2N (CH 3) 2
R 1Be H, OH, F, Cl, Br or I;
R 2Be by R 6The benzyl, (CH that replace 2) 2-O-is to cyano-phenyl, CH 2-O-to cyano-phenyl or CH=CH-O-to cyano-phenyl;
R 3Be H, CH 3, halogenide, CN or NO 2
R 4And R 5Be H, CH independently 3, halogenide, OH, C 1-4Alkyl, C 1-6Cycloalkyl, halo-C 1-4Alkyl, phenyl, aryl, heterocycle or hydroxyl-C 1-4Alkyl; And
R 6Be CN, NO 2, NHC (O) CH 3Or halogenide.
109. the compound of claim 108, wherein said compound is represented by the structure of formula XLVIII:
Figure A2007800347010027C1
110. the compound of claim 108, wherein said compound is represented by the structure of formula XLIX:
Figure A2007800347010027C2
111. the compound of claim 108, wherein said compound is represented by the structure of formula L:
Figure A2007800347010027C3
112. the compound of claim 108, wherein said compound is represented by the structure of formula LI:
113. the compound of claim 108, wherein said compound is represented by the structure of formula LII:
Figure A2007800347010028C2
114. pharmaceutical composition, it comprises compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of claim 1; And suitable carriers or thinner.
115. pharmaceutical composition, it comprises compound and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of the claim 1 of significant quantity; And pharmaceutically acceptable carrier, thinner or salt.
116. method of contraception in male, described method comprises to the effective compound of the claim 1 of the amount of sperm generation in the described individuality and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination of suppressing of described individual administration, is implemented in the contraception in the described individuality thus.
117. comprising, methods of hormonal treatment, described method make individual androgen receptor and the compound of the claim 1 of the amount that effectively realizes change androgen-dependent illness and/or the step that its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination contact.
118. the method for individuality of prostate cancer is suffered from treatment, described method comprises to described individual the administration effectively compound of the claim 1 of the amount of the prostate cancer in the described individuality of treatment and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
119. delay to suffer from the method for progress of prostate cancer of the individuality of prostate cancer, described method comprises to described individual administration and effectively delays the compound of the claim 1 of the amount of the progress of prostate cancer in the described individuality and/or the step of its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
120. the illness that the individual bone photo of treatment closes or increase individual bone amount, promote individual osteoplastic method, described method comprise to described individual the administration effectively compound of the claim 1 of the amount of the described bone photo of the treatment illness of closing or the step of its isomer, pharmacy acceptable salt, medicine, crystal, hydrate, N-oxide compound or their arbitrary combination.
121. the method for claim 120, wherein said individuality are suffered from osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility, bone mineral density (BMD) is lost or their arbitrary combination.
122. the method for claim 120, wherein said method increases the bone strength of described individuality.
123. the method for claim 120, wherein said compound promoted or be enhanced to osteocyte and generate.
124. the method for claim 120, wherein said compound suppress osteoclast propagation.
125. the muscular atrophy of treatment individuality, the method that reduces its sickness rate, delays its progress, alleviates its seriousness or alleviate relative symptom, described method comprise to the compound of the claim 1 of the amount of the described muscular atrophy of the described individuality of the effective treatment of described individual administration or the step of its isomer, pharmacy acceptable salt, medicine, crystal, hydrate, N-oxide compound or their arbitrary combination.
126. the method for claim 125, wherein said muscular atrophy is owing to symptom, illness, disease or illness.
127. the method for claim 126, wherein said symptom, illness, disease or illness are neuropathic, infective, chronic or genetic.
128. the method for claim 126, wherein said symptom, illness, disease or illness are muscular dystrophy, myatrophy, X spinobulbar muscular atrophy (SBMA), emaciation, malnutrition, leprosy, diabetes, nephropathy, chronic obstructive pulmonary disease (COPD), cancer, whole latter stage renal failure, Sarcopenia, pulmonary emphysema, osteomalacia, HIV infection, AIDS or myocardosis.
129. the method for claim 126, wherein said muscular atrophy are relevant muscular atrophies of age, and be useless in the relevant muscular atrophy of sexual maladjustment; Perhaps described muscular atrophy is owing to chronic low back pain, burn, central nervous system (CNS) damage or infringement, peripheral nerve injury or infringement, Spinal injury or infringement, chemical lesion or infringement or alcoholism.
130. treatment human individual's diabetes, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
131. the human individual's that suffers from of treatment glucose intolerance, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
132. treatment human individual's hyperinsulinemia, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
133. treatment human individual's insulin resistant, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
134. treat the disease relevant with diabetes, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
135. treatment human individual's fatty liver disease, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
136. treatment human individual's cardiovascular disorder, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
137. the individual emaciation of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
138. the method for claim 137, wherein said emaciation is relevant with the cancer of described individuality.
139. the individual rheumatoid arthritis of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
140. the individual chronic nephropathy of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
141. the individual end stagerenaldisease of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
142. the individual fragility of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
143. the individual hypogonadism of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
144. the relevant hypofunction of individual age of treatment, alleviate its seriousness, reduce its sickness rate, delay its outbreak or reduce the method for its morbidity, described method comprises the step to the compound of described individual administration claim 1 and/or its isomer, pharmacy acceptable salt, medicine, crystal, N-oxide compound, hydrate or their arbitrary combination.
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