CN101558058A - Modulators of CB1 receptors - Google Patents
Modulators of CB1 receptors Download PDFInfo
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- CN101558058A CN101558058A CNA2007800465454A CN200780046545A CN101558058A CN 101558058 A CN101558058 A CN 101558058A CN A2007800465454 A CNA2007800465454 A CN A2007800465454A CN 200780046545 A CN200780046545 A CN 200780046545A CN 101558058 A CN101558058 A CN 101558058A
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Abstract
Compounds of formula (I) suppress the normal signalling activity CB1 receptors, and are thus useful in the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity, such as treatment of obesity and overweight, prevention of weigh gain, treatment of diseases and conditions directly or indirectly associated with obesity and overweight: wherein A1 is hydrogen, -COOH, or tetrazolyl, and A2 is hydrogen, -COOH, or tetrazolyl, provided that one of A1 and A2 is either -COOH or tetrazolyl; p is O or 1 and A3 is phenyl or cycloalkyl, either of which is optionally substituted with R4 and/or R5; q is O or 1; R3 is hydrogen, C1-C4 alkyl, cycloalkyi, -CF3, or -OR9; R4 and R5 independently -R9, -CN, -F, -Cl, -Br, -OR9, - NR7R8, -NR7COR6, -NR7SO2R6, -COR6, -SR9, -SOR9, or -SO2R6; R6 is C1-C4 alkyl, cycloalkyl, -CF3 or -NR7R8; R7 and R8 are independently hydrogen, C1-C4 alkyl, -CF3, or cycloaikyL R9 is hydrogen, C1-C4 alkyl, cycloalkyl, fully or partially fluorinated C1-C4 alkyl; R1 is (i) a bond, or (ii) -(CH2)aB1(CH2)b- wherein a and b are independently O, 1, 2 or 3 provided that a+b is 1, 2 or 3; or (iii) -C(R10)(R11)-*, -C(R10)(R11)-O-*. -C(R10)(R11)CH2-*, -C(R10)(R11)CH2-O-*, - CH2C(R10)(R11)-*, -CH2C(R10)(R11)-O-*, -CH2-O-C(R10)(R11)-* or -C(R10)(R11)-O-CH2-*, wherein the bond indicated by an asterisk is attached to the pyrazole ring; R2 is a divalent radical of formula -Q1A4-[Q2]w- wherein Q1, A4, Q2 and w are as defined in the specification; and R10 is hydrogen and R11 is (C1-C3)alkyl or -OH; or R10 and R11 are both (C1-C3)alkyl; or R10 and R11 taken together with the carbon atom to which they are attached form a (C3- C5)cycloalkyl ring.
Description
The present invention relates to as cannaboid (cannabinoid) acceptor CB1 conditioning agent and the normal signal that the suppresses this acceptor active compound of transduceing.The invention still further relates to and use this compounds for treating to be subjected to the disease of the active mediation of CB1 receptor signal transduction or the composition and the method for illness, as treat fat and overweight, the prevention weight increase, treatment and fat and overweight directly or indirectly relevant disease and symptom such as metabolism syndrome, diabetes B, cardiovascular disorder, fat, metabolic function overweight or that normal type is individual is unusual, metabolic disease or metabolism disorder, cancer, hepatopathy and other secondary diseases of mentioning below, and treat some not necessarily with fat and overweight diseases associated, as eating disorder disease, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, reproductive function obstacle, hepatopathy, fibrillation related disease and other clinical indications of mentioning below.The invention still further relates to the pharmaceutical composition that contains The compounds of this invention, and the other treatment method that relates to this disease is used in combination this compound.
Background of invention
The fat morbidity of North America and most of European countries increased more than one times in the past in 20 years and has had now overweight or fat above the grownup of half.Fat holistic health problem (non-lattice (Fiegal) etc., 1998, Int.J.Obesity 22:39-47, mark big (Mokdad) etc., 1999, the JAMA 282:1519-1522 that is considered to a kind of chronic disease and a kind of danger now; Halford, 2006, Appetite, 46,6-10).Fat " can recognize S﹠S " comprises that the excessive accumulation of fat or fatty tissue, the volume or the quantity of adipocyte increase (adipocyte differentiation), insulin resistance, glucose level rising (hyperglycemia), elevation of blood pressure, cholesterol and triglyceride levels rising and hdl level reduction.The risk of the somatic death rate that fat and diabetes B, coronary heart disease, apoplexy, hypertension, various types of cancer and many other principal diseases and all reasons cause significantly rising relevant (horse looks spy (Must) etc., 1999, JAMA 282:1523-1529, card power (Calle) etc., 1999, N.Engl.J.Med.341:1097-1105).The a group metabolism risks and assumptions of cardiovascular disorder and diabetes B is commonly called metabolism syndrome, X syndrome or insulin resistant syndrome.The main composition of metabolism syndrome X comprises: stomach fat is (being also referred to as internal organ obesity, women obesity or apple shape obesity) too much, cause that atheromatous dyslipidemia (high density lipoprotein cholesterol (HDL-C) reduction), triglyceride level raise), hypertension, hyperglycemia (diabetes B or fasting impaired, the impaired or insulin resistance of glucose tolerance), short inflammatory states and short thrombus (prothrombotic) state are (with reference to AHA/NHLBI/ADA minutes, 2004; 109:551-556).Usually relevant with metabolism syndrome other comprise unusually: apolipoprotein B concentrates, the adiponectin blood plasma level is low, little fine and close low-density lipoprotein (LDL) particle, hyperuricemia, non-alcoholic fatty liver disease/fatty degeneration of liver, liver transaminase, gamma-glutamyl-transferring enzyme and microalbuminuria raise.
As fat, the morbidity of obesity-related disease such as diabetes also continues to raise.It is very crucial to lose weight for the obese patient, this can improve cardiovascular and thereby metabolic function reduces fat morbidity associated and mortality ratio (cloth guest cloth grace (Blackburn), 1999, Am.J.Clin.Nujtr.69:347-349, the real card in coffee road (Galuska) etc., 1999, JAMA 282:1576).The known 5-10% of losing weight can significantly improve such as glucose level, HbA after fasting and the feed
1Metabolism parameters such as c (HbAlC), Regular Insulin, total plasma cholesterol, low-density lipoprotein (LDL), triglyceride level, uric acid and blood pressure also reduce the developing risk (Gu win victory (Goldstein) of diabetes, cancer and cardiovascular disorder, 1992, J.Obesity, 6,397-415).
Therefore, a treatment main purpose fat and obesity-related disease is a loss of weight.At first, treat the change that is based on diet and mode of life and add pharmacological agent.Yet, although physical activity and reduce calorie to take in and can improve fat situation, since habitually mode of life and the high food of excessive diet, especially lipid content, the non-constant of the conformability of this treatment.In addition, the treatment of carrying out with existing diet pill is owing to have side effect, contraindication or lack and just respond and can't provide suitable benefit for most of obese patients.Therefore, press for the method for developing new and different treatment obesities.
Studied at present some possible diet pill (look back visible Bays, 2004, Obesity Research, 12,1197-1211) as:
I) the affect the nerves central nervous system medicament (thymoleptic (Bupropion) for example of mediator or neural ionic channel, norepinephrine reuptake inhibitor (GW320659), selectivity 5HT 2c receptor stimulant, antiepileptic drug (topiramate, zonisamide), some dopamine antagonist, cannaboid CB-1 receptor antagonist (Rimonabant);
Ii) Leptin/Regular Insulin/central nervous system approach medicine (Leptin analogue for example, Leptin transhipment and/or receptor promoter, CNTF (Ai Suoxin (Axokine)), the NPY antagonist, the AgRP antagonist, the POMC promotor, the CART promotor, the MSH analogue, the MC4 receptor stimulant influences insulin metabolism/active medicament [PTP-1B inhibitor, the PPAR receptor antagonist, short effect D2 agonist (Ergotamine), somatostatin agonists (Sostatin), and adiponectin/Acrp30 (Fa Moxin (Famoxin) or fatty acid metabolism oxidation inductor)]);
Iii) stomach and intestine-neural approach medicament (for example improves the active medicament of CCK and PYY, improve the active medicament of GLP-1 (Ai Tanting (extendin) 4, Li Lalu peptide (liraglutide), inhibitors of dipeptidyl IV), reduce the active medicament of ghrelin, islet amyloid polypeptide (tripro-amylin), neuropeptide Y agaonists);
Iv) improve the medicament (beta-3 agonist, UCP homologue, thryoid receptor agonist) of resting metabolic rate; With
V) more other reagent, for example comprise (MCH) melanin concentration hormone antagonist, the similar thing of plant sterol, functional oil (functional oil), P57, amylase inhibitor, growth hormone fragment, the synthetic analogues of DHEAS (not Esther ketone (fluasterone)), the active antagonist of 1 type adipocyte 11beta-Hydroxysteroid dehydrogenase, the CRH agonist, carboxyl peptide enzyme inhibitor, lipid acid synthetic inhibitor (cerulenin and C75), indone/indanol, amino steroid (bent Da Kemai (trodusquemine)) and other gastrointestinal lipase inhibitor (ATL962).
Effectively the fat medicine of treatment can play a role by various mechanism, for example by reducing ingestion of food (for example by inducing satiety or satiety signal), change metabolism (for example passing through to change the absorption of nutrient substance) as passing through to suppress fat absorbing, increase energy expenditure (for example increasing heat production), suppress steatogenesis or stimulate the adipocyte apoptosis.Yet, only can obtain few diet pill (look back (Gadde) and the A Lisen (Allison) of visible coffee, 2006, Circulation, 114,974-984; Lattice (Weigle) not, 2003, J Clin Endocrinol Metab., 88,2462-2469; This its speed (
), 2006, CNS Neurol.Disorders Drug Targets, 5,241-249).Sibutramine is a kind of thrombotonin and norepinephrine presynaptic reuptake mixed inhibitor that acts on central nervous system.Orlistat is a kind of gastrointestinal lipase inhibitor that reduces the intestines and stomach fat absorbing.Rimonabant (SR
141716,
) be a kind of unify cannabinoid CB 1 conditioning agent (antagonist and inverse agonist) of peripheral nervous system of central nervous system that acts on, be approved for recently treatment fat (look back visible Pa Getuo (Pagotto) etc., 2006, Endocrine Reviews, 27,73-100; The visible Tippi of relevant its III phase clinical report real (Despres) etc., 2005, N.Engl.J.Med.353,212; Model jar (unit of capacitance) (van Gaal) etc., 2005, Lancet, 16,1389; Pi-Su is (Pi-Sunyer) etc., and 2006, JAMA, 295,761).
Two kinds of Cannabined receptor: CB1 have been characterized at present, a kind of acceptor of finding at many other positions of Mammals brain and peripheral tissues; And CB2, a kind of peripheral acceptor of mainly in the immunity system relevant cell, finding.About bodhi not (Pertwee), 2000, Exp.Opin are seen in the review of cannabinoid CB 1 and CB2 receptor modulators.Invest.Drugs, 9,1553-1571 and eye vision (Muccioli), 2005, Cur.Med.Chem., 12,1361-1394.Have a lot of evidence proof CB1 antagonists (for example Rimonabant) can regulate the energy homeostasis, the CB1 antagonist can be regulated ingestion of food and periphery blocking-up steatogenesis process (Pa Getuo (Pagotto) etc., 2006, Endocrine Reviews, 27,73-100; Toast (Tucci) etc., 2006, Curr.Med.Chem.13,2669-2680; Lan Qi (Lange) but and road this (Kruse), 2004, Current Opinion in Drug Discovery; Dev., 7,498-506).Some target organs and mechanism can mediate the periphery effect of CB1 antagonist, i for example) liver: from the beginning blocking-up fat generate, ii) muscle: increase glucose uptake, iii) fatty tissue: stimulate adiponectin to express and/or secretion, suppress the steatogenesis enzyme, stimulate GLUT4, produce invalid circulation, iv) pancreas: regulate Regular Insulin and v) gi tract: stimulation satiety signal.
Rimonabant
Go through to be used for the treatment of obesity as the method outside diet and the exercise.Although for body weight and metabolizing parameters (plasma triglyceride level, HDL cholesterol levels, plasma insulin level, HbA
1The c[HbAlC] level, insulin resistance, with the adiponectin level) influence very exciting, but undesirable side effect is also arranged, and this side effect may be (psychosis and the nervous system disorders) of central nervous system mediation, as anxiety, dysthymia disorders, somnopathy is felt sick, and vomiting (reference
Http:// emc.medicines.org.ukHttp:// www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/Acomplia EparScientificD-en.pdf).Therefore, still need to have different pharmacokineticss, other CB1 receptor antagonists of pharmacology and side effect feature.
Known CB1 acceptor participation numerous disease state (handkerchief car (Pacher) etc. is seen in review, 2006, and Pharmacol.Rev, 58,389-462).The CB1 receptor activity modulators can be used for treating with the CB1 acceptor regulates relevant disease and symptom as obesity and overweight, prevention weight increase (for example medicine or smoking cessation inductive weight increase), and treatment and fat direct or indirect relevant disease and symptom are (with reference to cloth flower bud (Bray), 2004, J.Clin.Endocrinol.Metab.89,2583-9; Overflow gloomy (Manson), etc., 1995, N.Engl.J.Med.333,677-85; Ancient opinion (Grundy), 2004 .J.Clin.Endocrinol.Metab.89,2595-600; With honesty holder (Esposito) etc., 2004, JAMA 291; 2978-84; And cloth big (Ejerblad) of heap of stone etc., 2006; J.Am.Soc.Nephrol.17,695-702; White sprouts (Whitmer) etc., and 2005, BMJ 330 (7504), and 1360), as
-metabolism syndrome is also referred to as X syndrome or insulin resistant syndrome,
-diabetes B,
-cardiovascular disorder (aneurysma for example, angor, irregular pulse, atherosclerosis, myocardosis, cerebrovascular accident (apoplexy), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valvular heart disease, coronary heart disease, DCM (dilated cardiomyopathy), diastolic dysfunction, endocarditis, hypertension (hypertension), hypertrophic cardiomyopathy and relevant irregular pulse and dizziness thereof, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varix and pulmonary infarction, short inflammatory states, thrombosis risk increase (short thrombus sexual state) and intracranial hypertension
-fat, overweight or metabolic function that normal type is individual unusual (dyslipidemia for example, hyperlipidaemia, low HDL and/or high LDL cholesterol levels, hypertriglyceridema, low fat connects protein level, the glucose tolerance is impaired, insulin resistance, HbA
1The c[HbAlC] the level rising, diabetes, diabetes B, metabolic activity reduces),
-metabolic disease or metabolism disorder (abnormal metabolism process symptom that derive or that cause; Can be geneogenous (because the heredity enzyme is unusual) or acquired (because depletion of metabolism vitals such as endocrine organ's disease or liver),
-cancer (for example colorectal carcinoma, mammary cancer, uterus carcinoma, colorectal carcinoma),
-hepatopathy (for example non-alcoholic fatty liver disease, fatty liver, steatosis, hepatic fibrosis, liver cirrhosis) and
-with fat and overweight other relevant secondary diseases, as menoxenia, gastroesophageal reflux disease, cholelithiasis (cholelith), hernia, the urinary incontinence, chronic renal failure, hypogonadism (male sex), stillbirth, stretch marks (stretchmarks), acanthosis nigricans, lymphedema, cellulitis, carbuncle, intertrigo, hyperuricemia, motionless, osteoarthritis, lumbago and backache, meralgia paraesthetica, headache, carpal tunnel syndrome, dementia, the special property sent out expiratory dyspnea, obstructive sleep apnea, hypoventilation syndrome, pickwickian syndrome, asthma, depression, low oneself respects, health abnormity disease, and society is described.
Known CB1 acceptor participate in many not necessarily with fat and overweight diseases associated or morbid state, as
-eating disorder disease,
-addictive disorders (for example to hemp, psychostimulant, Nicotine, alcohol, Cocaine and narcotism),
-mental disorder (for example schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, panic disorder),
-neurological disorder,
-sexual dysfunction (for example erectile dysfunction),
-reproductive function obstacle (for example polycystic ovarian syndrome, infertility),
-hepatopathy (for example, virusology hepatitis, the dysfunction of liver in other infectious diseases, inflammatory hepatopathy (for example autoimmune hepatitis), alcoholic liver disease, toxic hepatic disease, liver tumor is (as liver cell cancer, hepatocellular carcinoma, liver cancer, cholangiocarcinoma, hepatoblastoma, liver vessel sarcoma, the Kupffer cell cancer, other hepatosarcoma), fatty liver, the non-alcoholic fatty liver disease hepatic fibrosis, liver cirrhosis, cirrhotic portal hypertension, the metabolic hepatopathy is (as hemochromatosis, hepatolenticular degeneration, gilbert's syndrome, crigler-Najjar syndrome, Dubin Johnson syndrome, rot's syndrome))
-fibrillation related disease (as pancreas and lung sac fibrosis, myocardium endocardium fibrosis, idiopathic cardiomyopathy, idiopathic pulmonary fibrosis, the substantive tuberculosis of dispersivity, mediastinal fibrosis, myelofibrosis, the postvasectomy pain syndrome, retroperitoneal fibrosis, PMF, fibrosis proliferativa, fibrosis proliferativa, sicklemia can cause spleen to enlarge and final fibrosis)
-and other clinical indications such as epilepsy, osteoporosis, rheumatoid arthritis, inflammatory bowel (ulcerative colitis (UC) and Crohn's disease (CD), congested obstructive pulmonary disease (COPD), inflammation, inflammatory pain, atherosclerosis, diarrhoea, asthma, constipation, tetter, glaucoma and shaving one's head.
Since fat can cause the comorbidities of various body systems or significantly improve its risk (see Bays, 2004, Obesity Research, 12,1197-1211), also be useful with the drug regimen that is used for the treatment of these diseases therefore with the CB1 conditioning agent, described disease comprises:
I) cardiovascular (hypertension, congestive cardiomyopathy, varix, pulmonary infarction, coronary heart disease [CHD], sacred disease (apoplexy, special property intracranial hypertension, the meralgia parasthetica sent out),
Ii) respiratory illness's (expiratory dyspnea, obstructive sleep apnea, hypoventilation syndrome, pickwickian syndrome, asthma),
Iii) musculoskeletal disease (motionless, degenerative osteoarthritis, lumbago and backache),
Iv) skin also (striae atrophicae or " stretch marks ", veins of lower extremity are retarded by silt, lymphedema, cellulitis, intertrigo, carbuncle, acanthosis, skin is superfluous),
V) gastrointestinal illness (gastroesophageal reflux disease, non-alcoholic fatty liver disease/fatty liver, cholelithiasis, hernia, colorectal carcinoma),
Vi) urogenital disease (stress incontinence, fat relevant glomerulopathy, mammary cancer and uterus carcinoma),
Vii) mental illness (depressed and low oneself respects, and quality of life is low), and
Viii) endocrinopathy (metabolism syndrome, diabetes B, dyslipidemia, women's hyperandrogenism, polycystic ovarian syndrome, dysmenorrhoea, infertility, pregnancy complications, male hypogonadism)
May and may also be useful with the drug regimen of irrelevant other clinical indications of obesity with the CB1 conditioning agent with the irrelevant disease of obesity such as eating disorder disease, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, reproductive function obstacle, hepatopathy, fibrillation related disease with being used for the treatment of.
Summary of the invention
The invention provides a class and regulate the active pyrazole compound of Cannabined receptor CB1.Below announce to relate to and have active other pyrazole compounds of CB1 adjusting:
WO1997021682，WO1997019063，WO2000046209，WO2001058869，WO200129007，WO2003088968，WO2003020217，WO2004052864，，WO2005080343，WO2006067443，WO2006087480，WO?2006133926，EP00576357，EP00658546，US20030199536，US20040119972，US20040192667，US20050261281，US20050624941，US2006028084，US20060509367，J.Med.Chem.199942，769-776，Biochem.Pharmacol，2000，60，1315-1323，J.Med.Chem.2003，46，642-645，Bioorg?&?Med.Chem.Lett.2004，14，2393-2395，Current?Med.Chem.2005，12，1361-1394。
As mentioned above, The compounds of this invention is used for the treatment of fat and overweight, the prevention weight increase, and be used for the treatment of the above-mentioned normal signal of benefiting from inhibition CB1 acceptor transduce active disease and symptom.As mentioned above, that this disease and symptom comprise is fat and overweight, with obesity and overweight direct or indirect those relevant diseases and illness (metabolism syndrome for example, diabetes B, cardiovascular disorder, metabolic disease, cancer, hepatopathy and other secondary diseases) and some may with the irrelevant disease of obesity and illness (eating disorder disease for example, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, reproductive function obstacle, hepatopathy, fibrillation related disease and other clinical indications).They are used to regulate mammiferous body weight and energy expenditure, are used to regulate the plasma parameters such as low HDL and/or high LDL cholesterol levels and/or the little fine and close LDL particle that relate to metabolism syndrome, and high triglyceride level, low fat connect protein level and high HbA
1The c[HbAlC] level, other features such as the glucose tolerance that are used to regulate metabolism syndrome are impaired, fatty tissue is too much on every side with belly in the insulin resistance, abdomen, non-alcoholic fatty liver disease, fatty liver, steatosis, hepatic fibrosis, liver cirrhosis, liver tumor, metabolic hepatopathy and hypertension.
The compounds of this invention demonstrate different physico-chemical properties and for regulate periphery CB1 acceptor and in various degree maincenter CB1 acceptor be effective.Those compounds of the present invention are lower to the central action of CB1 acceptor, can reduce the tendency of inducing neurological and neural system side effect.
International Patent Application PCT/the EP2005/005726 that awaits the reply relates to the compound that has the CB1 receptor modulating activities shown in the following formula:
Wherein
A
1Be hydrogen ,-COOH or tetrazyl, A
2Be hydrogen ,-COOH, tetrazyl ,-CN ,-CF
3,-COR
6,-SO
2R
6,-OR
7,-NR
7R
8,-NHCOR
6, or-NR
7SO
2R
8, prerequisite is A
1And A
2One of be-COOH or tetrazyl;
P is 0 or 1, A
3Be phenyl or cycloalkyl, arbitrary choosing wantonly by R
4And/or R
5Replace;
Q is 0 or 1;
R
1Be key or-(CH
2)
aB
1(CH
2)
b-, wherein a and b independently are 0,1,2 or 3, prerequisite is that a+b is not more than 4, and B
1Be-CO-,-O-,-S-,-SO-,-SO
2-,-CH
2-,-CHOH-or-NR
7-.
R
2Be key ,-(CH
2)
aB
1(CH
2)
b-or-[(CH
2)
aB
1(CH
2)
b]
n-A
4-[(CH
2)
cB
2(CH
2)
d]
m-, wherein, a, b and B
1As at R
1In definition; B
2As at B
1In definition, c and d independently are 0,1,2 or 3; Prerequisite is that a+b+c+d is not more than 6, and n and m independently are 0 or 1, and A
4Be optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In monocyclic carbocyclic ring or single heterocycle of one or more replacements;
R
3Be hydrogen, C
1-C
4Alkyl, cycloalkyl ,-CF
3,-OR
9,-NR
7R
8,-(CH
2)
sCOR
6,-(CH
2)
sSO
2R
6,-(CH
2)
sNR
7COR
6,-(CH
2)
sNR
7COOR
8,-(CH
2)
sNR
7SO
2R
6, wherein, s is 1,2,3 or 4;
R
4And R
5Independently be-R
9,-CN ,-F ,-Cl ,-Br ,-OR
9,-NR
7R
8,-NR
7COR
6,-NR
7SO
2R
6,-COR
6,-SR
9,-SOR
9,-SO
2R
6,-(C
1-C
4Alkyl) OR
9,-(C
1-C
4Alkyl) NR
7R
8,-(C
1-C
4Alkyl) NR
7COR
6,-(C
1-C
4Alkyl) NR
7COOR
8,-(C
1-C
4Alkyl) NR
7SO
2R
6,-(C
1-C
4Alkyl) COR
6,-(C
1-C
4Alkyl) SO
2R
6,-NR
7COOR
8, or-[N-(C
1-C
4Alkyl)]-tetrazyl;
R
6Be C
1-C
4Alkyl, cycloalkyl ,-CF
3Or-NR
7R
8
R
7And R
8Independent is hydrogen, C
1-C
4Alkyl or cycloalkyl; With
R
9Be hydrogen, C
1-C
4Alkyl, cycloalkyl, fluorizated C wholly or in part
1-C
4Alkyl.
Those compounds are structurally different among compound involved in the present invention and the PCTEP2005/005726, mainly are-R
1-Ji and/or-N (R
2)-R
3-A
2The homogeny of base.
Detailed Description Of The Invention
According to a first aspect of the invention, provide the compound of a kind of formula (IB), or its salt, hydrate, solvate, single enantiomorph or N-oxide compound:
Wherein:
A
1Be hydrogen ,-COOH or tetrazyl;
P and q independently are 0 or 1;
A
3Be phenyl or cycloalkyl, arbitrary choosing wantonly by R
4And/or R
5Replace;
R
4And R
5Independently be-R
9,-CN ,-F ,-Cl ,-Br ,-OR
9,-NR
7R
8,-NR
7COR
6,-NR
7SO
2R
6,-COR
6,-SR
9,-SOR
9Or-SO
2R
6
R
6Be C
1-C
4Alkyl, cycloalkyl ,-CF
3Or-NR
7R
8
R
7And R
8Independent is hydrogen, C
1-C
4Alkyl or cycloalkyl;
R
9Be hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkoxyl group (C
1-C
4Alkyl)-, cycloalkyl, fluorizated C wholly or in part
1-C
4Alkyl;
R
1Be
(i) key, or
(ii)-(CH
2)
aB
1(CH
2)
b-, wherein, a and b independently are 0,1,2 or 3, prerequisite is that a+b is not more than 4, and B
1Be-CO-,-O-,-S-,-SO-,-SO
2-,-CH
2-,-CHOH-or-NR
7-; Or
(iii) be selected from down the divalent radical of group :-C (R
10) (R
11)-
*,-C (R
10) (R
11)-O-
*,-C (R
10) (R
11) CH
2-
*,-C (R
10) (R
11) CH
2-O-
*,-CH
2C (R
10) (R
11)-
*,-CH
2C (R
10) (R
11)-O-
*,-CH
2-O-C (R
10) (R
11)-
*With-C (R
10) (R
11)-O-CH
2-
*, wherein, the key of representing with asterisk is connected in the pyrazoles ring;
R
10Be hydrogen, R
11Be (C
1-C
3) alkyl; Or R
10And R
11All be (C
1-C
3) alkyl; Or R
10And R
11Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring; With
Group-N (R
3) R
2-A
2Have formula (II), (III), (IV) or (V):
Wherein, x and y independently are 0 or 1, and k is 1 or 2, and j is 1,2,3 or 4.
B
3Be-C (R
13) (R
14)-,-O-or-NR
7-or arbitrary orientation-O-C (R
13) (R
14)-,-CH
2-C (R
13) (R
14)-;
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-.
A
2Be hydrogen ,-COOH, tetrazyl ,-CN ,-CF
3,-COR
6,-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6, prerequisite is A
1And A
2One of be-COOH or tetrazyl;
A
4Be optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the monocycle carbocyclic ring or the monocyclic heterocycles of one or more replacements;
Ring A be optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocycle carbocyclic ring or the monocyclic heterocycles of one or more replacements; With
R
13And R
14Independent is hydrogen or (C
1-C
3) alkyl; Or R
13And R
14All be (C
1-C
3) alkyl; Or R
13And R
14Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring.
In the invention described above aspect first in described compound:
R
9Can be hydrogen, C
1-C
4Alkyl, cycloalkyl, fluorizated C wholly or in part
1-C
4Alkyl; With
B
4Can be-C (R
13) (R
14)-,-CO-or-SO
2-.
Therefore, the present invention includes the compound of formula (I), or its salt, hydrate, solvate, single enantiomorph or N-oxide compound:
Wherein:
A
1Be hydrogen ,-COOH or tetrazyl;
P and q independently are 0 or 1;
A
3Be phenyl or cycloalkyl, arbitrary choosing wantonly by R
4And/or R
5Replace;
R
4And R
5Independently be-R
9,-CN ,-F ,-Cl ,-Br ,-OR
9,-NR
7R
8,-NR
7COR
6,-NR
7SO
2R
6,-COR
6,-SR
9,-SOR
9, or-SO
2R
6
R
6Be C
1-C
4Alkyl, cycloalkyl ,-CF
3Or-NR
7R
8
R
7And R
8Independent is hydrogen, C
1-C
4Alkyl or cycloalkyl
R
9Be hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkoxyl group (C
1-C
4Alkyl)-, cycloalkyl or fluorizated C wholly or in part
1-C
4Alkyl;
R
1Be
(i) key;
(ii) formula-(CH
2)
aB
1(CH
2)
b-divalent radical, wherein, a and b independently are 0,1,2 or 3, prerequisite is that a+b is 1,2 or 3, and B
1Be-CO-,-O-,-S-,-SO-,-SO
2-,-CH
2-,-CHCH
3-,-CHOH-or-NR
7-; Or
(iii) be selected from down the divalent radical of group :-C (R
10) (R
11)-
*,-C (R
10) (R
11)-O-
*,-C (R
10) (R
11) CH
2-
*,-C (R
10) (R
11) CH
2-O-
*,-CH
2C (R
10) (R
11)-
*,-CH
2C (R
10) (R
11)-O-
*,-CH
2-O-C (R
10) (R
11)-
*With-C (R
10) (R
11)-O-CH
2-
*, wherein, the key of representing with asterisk is connected in the pyrazoles ring;
Z is selected from morpholine-1-base and formula (II), (III), (IV) and group (V)
Wherein,
X and y independently are 0 or 1,
K is 1 or 2;
J is 1,2,3 or 4.
A
2Be hydrogen ,-COOH, tetrazyl ,-CN ,-CF
3,-COR
6,-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6, prerequisite is to work as A
1A when being hydrogen
2Be-COOH or tetrazyl,
A
4Be key, or
(i) have 3-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocycle carbocyclic ring of one or more replacements; Or
(ii) have 4-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocyclic heterocycles of one or more replacements,
The prerequisite of formula (IV) is to work as A
4When being key, B
3Be not connected in A by oxygen or nitrogen
4
B
3Be-C (R
13) (R
14)-,-O-or-NR
7-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-,
The prerequisite of formula (II)-(V) is, when x is 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A then
2Be hydrogen;
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-;
Ring A is:
(a) have 3-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocycle carbocyclic ring of one or more replacements; Prerequisite be when A be not that aromatic series, x are 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A
2Be hydrogen; Or
(b) have 3-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocyclic heterocycles of one or more replacements; Prerequisite be when A be not that aromatic series, x are 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A
2Be hydrogen;
R
10Be hydrogen, R
11Be (C
1-C
3) alkyl or-OH; Or R
10And R
11All be (C
1-C
3) alkyl; Or R
10And R
11Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring; With
R
13And R
14Independent is hydrogen or (C
1-C
3) alkyl; Or R
13And R
14All be (C
1-C
3) alkyl; Or R
13And R
14Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring.
Another aspect of the present invention is a kind of compound or its salt, hydrate, solvate or the N-oxide compound of formula (I) and pharmaceutical composition of one or more pharmaceutically acceptable carriers or vehicle of comprising.
For the compound of the Orally-administrable that the present invention relates to, according to known drug chemistry principle, the maximum molecular weight of preferred compound is 750, perhaps more effectively is 650 to the maximum.
Compound involved in the present invention suppresses the normal signal transduction activity of Cannabined receptor CB1.Therefore, other aspects of the present invention are:
(i) compound or its salt of formula (I), hydrate, solvate or N-oxide compound are used for the treatment of application in the composition of the disease that is subjected to the active mediation of CB1 receptor signal transduction or illness in preparation.The example of this disease is listed hereinbefore; With
(ii) a kind of treatment is subjected to the disease of the active mediation of CB1 receptor signal transduction or the method for illness, and this method method comprises compound or its salt, hydrate, solvate or the N-oxide compound of the formula (I) of the object significant quantity of suffering from this disease or illness.Equally, the example of this treatment is listed hereinbefore.
Term
In the literary composition, term " (C
a-C
b) alkyl " refer to have the straight or branched alkyl of a to b carbon atom, wherein a and b are integers.Therefore, for example, when a is 1 and b when being 6, this term comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl and n-hexyl.
Used term " carbocyclic ring " is meant that being up to 16 all is monocycle base, two cyclic groups or three cyclic groups of the annular atoms of carbon, comprises aryl and cycloalkyl in the literary composition.
Used term " cycloalkyl " is meant the monocycle saturated carbon cyclic group with 3-8 carbon atom in the literary composition, comprise, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
Nonrestrictive term " aryl " used in the literary composition is meant monocyclic, bicyclic or tricyclic isocyclic aryl, comprises having two bases by the direct-connected monocycle carbocyclic ring of covalent linkage aromatic ring.The example of this class base is phenyl, xenyl and naphthyl.
Non-limiting term " heteroaryl " used in the literary composition is meant the heteroatomic monocyclic, bicyclic or tricyclic aryl that contains one or more S of being selected from, N and O, comprises having two these class monocycles that directly link to each other by covalent linkage or passing through directly continuous this class monocycle of covalent linkage and the base of a monocyclic aromatic rings.The example of this class base is thienyl, benzothienyl, furyl, benzofuryl, pyrryl, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazole base, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridyl, pyridazinyl, pyrimidyl, triazinyl, indyl and indazolyl.
Non-limiting term " heterocyclic radical " or " heterocyclic " used in the literary composition comprise as defined above " heteroaryl ", also refer to contain the heteroatomic monocyclic, bicyclic or tricyclic non-aromatic group of one or more S of being selected from, N and O, and by contain one or more non-aromatic groups of this heteroatomic monocycle and another this base or with the covalently bound group of forming of monocycle carbocylic radical.The example of this class base is pyrryl, furyl, thienyl, piperidyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, pyrazolyl, pyridyl, pyrrolidyl, pyrimidyl, morpholinyl, piperazinyl, indyl, morpholinyl, benzofuryl, pyranyl, isoxazolyl, benzimidazolyl-, methylenedioxyphenyl, ethylidene dioxy phenyl, dimaleoyl imino and succinimido.
Unless the place of Chu Xianing has explanation in addition in the text, the term " replacement " that is applied to any part in the literary composition is meant at most and replaced by four compatible substituting groups, and each substituting group is independently, for example, and (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, hydroxyl, hydroxyl (C
1-C
6) alkyl, sulfydryl, sulfydryl (C
1-C
6) alkyl, (C
1-C
6) alkylthio, halogen (comprising fluorine, bromine and chlorine), fluorizated (C wholly or in part
1-C
3) alkyl, (C
1-C
3) alkoxyl group or (C
1-C
3) alkylthio such as trifluoromethyl, trifluoromethoxy and trifluoromethylthio, nitro, itrile group (and CN), oxo, phenyl, phenoxy group, bicyclic heteroaryl or heteroaryloxy, tetrazyl with 5-6 annular atoms ,-COOR
A,-COR
A,-OCOR
A,-SO
2R
A,-CONR
AR
B,-SO
2NR
AR
B,-NR
AR
B, OCONR
AR
B,-NR
BCOR
A,-NR
BCOOR
A,-NR
BSO
2OR
AOr-NR
ACONR
AR
B, R wherein
AAnd R
BBe hydrogen or (C independently
1-C
6) alkyl, perhaps at R
AAnd R
BWhen linking to each other with same N atom, R
AAnd R
BForm the amino ring of ring as morpholine ring, piperidine ring or piperazine ring with this nitrogen-atoms together.When substituting group is a phenyl, phenoxy group or the bicyclic heteroaryl of 5 or 6 annular atomses is arranged or during heteroaryloxy, its phenyl or hetero-aromatic ring itself can be replaced by above-mentioned any substituting group except that phenyl, phenoxy group, heteroaryl or heteroaryloxy." optional substituting group " can be a kind of in the above-mentioned substituting group.
Term " salt " used in the literary composition comprises base addition salt, acid salt and quaternary ammonium salt.The compounds of this invention can form salt (comprising pharmacy acceptable salt) with following listed alkali: for example, alkali metal hydroxide is such as sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxides is such as calcium hydroxide, hydrated barta and magnesium hydroxide; Organic bases is such as N-methyl D-glycosamine, choline three (methylol) amino-methane, L-arginine, L-Methionin, N-ethylpiperidine, dibenzylamine etc.Those compounds (I) for alkalescence can form salt (comprising pharmacy acceptable salt) with following listed acid: mineral acid, for example, haloid acid example hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid etc.; Organic acid, for example acetate, tartrate, Succinic Acid, fumaric acid, toxilic acid, oxysuccinic acid, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, phenylformic acid, Phenylsulfonic acid, L-glutamic acid, lactic acid and amygdalic acid etc.
For look back " the pharmaceutical salts handbook: characteristic, selection and application " that visible Si Taha of suitable salt (Stahl) and wet wood this (Wermuth) writes (
Handbook of Pharmaceutical Salts:Properties, Selection, And Use)(German Willie press (Wiley-VCH, Weinheim, Germany), 2002).
Term ' solvate ' is used for describing the molecular complex of one or more pharmaceutically acceptable solvent molecules (as ethanol) that comprise The compounds of this invention and stoichiometry in the text.When being water, adopts by described solvent term ' hydrate '.
Owing to have asymmetric atom or rotation restriction, compound involved in the present invention can take one or more stereoisomeric forms in any ratio to exist, and can be used as manyly to have R or the stereochemical steric isomer of S or exist as have the stereochemical atropisomer of R or S at each chiral axis at each chiral centre.The present invention includes all these enantiomorphs and diastereomer and their mixture.
The compounds of this invention comprises the compound of formula defined above (I), comprise its all polymorphic forms and crystallized form, as hereinafter defined it prodrug and the compound of isomer (comprise optics, how much tautomers) and isotope-labeled formula (I).
' prodrug ' of the compound of so-called formula (I) is also within the scope of the invention.Therefore, some itself may have extremely low or the derivative of compound of formula (I) that do not have a pharmacological activity for example can change the compound with required active formula (I) into by the hydrolysis cutting in giving body or on the body time.This derivative is called as " prodrug ".The further information of using about prodrug can " prodrug-Xin delivery system " (
Pro-drugs as Novel Delivery Systems), the 14th volume, ACS symposium book series (ACS Symposium Series) (T. stops Gu and holds (T.Higuchi) and V.J. Si Tela (V.J.Stella)) and " the biological reversible carrier in the medicinal design " (
Bioreversible Carriers in Drug Design), Pa Jiameng press (Pergamon Press), 1987 (E.B.Roche volume, American Pharmaceutical Associations; C.S. draw unfamiliar to the ear (C.S.Larsen) and this special coffee of J.
Prodrug design and application (Design and application of prodrugs), be selected from " medicinal design and send handbook (Textbook of Drug Design and Discovery), the third edition, 2002, TF press (Taylor and Francis)).
For example, the suitable functionality that some part that available those skilled in the art are known to be called " precursor portions (pro-moiety) " replaces existing in the compound of formula (I) is come comfortable prodrug of the present invention, its description is seen, for example, " the prodrug design " write of the coffee of H. class (H.Bundgaard) (
Design ofProdrugs)(Yi Siweier press (Elsevier), 1985).This example can be that the carboxyl prodrug (uses-CO-O-CH in the pivampicillin prodrug as penbritin
2-O-CO-tBu), acid amides prodrug (CO-NH-CH
2-NAlk
2) or amidine prodrug (C (=N-O-CH
3)-NH
2).
Scope of the present invention also comprises the metabolite of the compound of formula (I), promptly gives the compound that forms in vivo behind the medicine.Some examples of metabolite comprise:
(i) when the compound of formula I contains methyl, its hydroxymethyl derivative (CH
3→-CH
2OH):
(ii) when the compound of formula I contains alkoxyl group, its hydroxy derivatives (OR →-OH);
(iii) contain uncle when amino, its secondary amino group derivative (NR when the compound of formula I
1R
2→-NHR
1Or-NHR
2);
(iv) when the compound of formula I contains secondary amino group, its primary amino derivative (NHR
1→-NH
2);
(v) when the compound of formula I contains phenyl, its phenol derivatives (Ph →-PhOH); With
(vi) when the compound of formula I contains amide group, its carboxylic acid derivative (CONH
2→ COOH).
For the application of the above-mentioned aspect of foundation the present invention, can there be the following constitutional features of taking any compatible array configuration in the compound (I):
GroupA
1
A
1Be-COOH or tetrazyl.
Group A
3
A
3Be phenyl or cycloalkyl, as cyclopentyl or cyclohexyl, optional by R
4And/or R
5Replace.At present preferred situation is A
3Be phenyl, optional by R
4And/or R
5Replace.Substituent R
4And/or R
5Definition hereinbefore, but at present preferred situation is them independently be selected from hydrogen ,-F ,-CN or-Cl, work as A
3When being phenyl or 6-unit heteroaryl, be connected in-(CH shown in the formula (I)
2)
q-phenyl ring A
3With in any R
4And R
5Substituting group will be usually located at the contraposition and/or the ortho position of those rings.For example, shown in formula (I), be connected in-(CH
2)
q-phenyl ring in R
4Can be hydrogen and R
5Can be hydrogen and at-(CH
2) contraposition of q-, and individually or with this characteristics combination, work as A
3When being phenyl or 6-unit heteroaryl, A
3In R
4Can be hydrogen and R
5Can not hydrogen and be positioned at-(CH
2) ortho position of p-.
Index p and q
Index p and q independently are 0 or 1, but at present preferred situation is that p and q respectively do for oneself 0.
Divalent radical R
1
R
1Definition hereinbefore.
When being not key, R
1Can be the divalent radical-(CH that defines as mentioned
2)
aB
1(CH
2)
b-.At this moment, B
1Can be, for example-CH
2-or-O-.R
1The object lesson of base comprises-CH
2-,-CH
2O-
*With-CH
2OCH
2-, wherein, the key of representing with asterisk is connected in the pyrazoles ring.
When being not key, R
1Base can also be the divalent radical that is selected from down group :-C (R
10) (R
11)-
*,-C (R
10) (R
11)-O-
*,-C (R
10) (R
11) CH
2-
*,-C (R
10) (R
11) CH
2-O-
*,-CH
2C (R
10) (R
11)-
*,-CH
2C (R
10) (R
11)-O-
*,-CH
2-O-C (R
10) (R
11)-
*With-C (R
10) (R
11)-O-CH
2-
*, wherein, the key of representing with asterisk is connected in the pyrazoles ring, and R wherein
10And R
11As hereinbefore defined.This R
10Base can be, for example, and hydrogen or methyl, and R
11Can be, for example, methyl.Such R
1The base object lesson comprise-CH (OH)-and-CH (CH
3)-.
Group Z
Z defines hereinbefore.
In a kind of type of at present preferred The compounds of this invention, Z has structural formula:
In the type of the at present preferred The compounds of this invention of another kind, Z has structural formula:
Wherein, the optional quilt-F of thick phenyl ring ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Replace.
Work as B
3When being present among the group Z, B
3Can be, for example ,-C (R
13) (R
14)-or arbitrary orientation-O-C (R
13) (R
14)-,-CH
2-C (R
13) (R
14)-or-NR
7-, wherein, R
13And R
14Independent is hydrogen or methyl; And R
7Be hydrogen, methyl or cyclopropyl;
Work as B
4When being present among the group Z, B
4Can be, for example ,-C (R
13) (R
14)-, wherein, R
13And R
14Independent is hydrogen or methyl.
Work as A
4When being present among the group Z, A
4Can be selected from (for example) group down: phenyl, pyridine, pyrimidine, thiophene, furans, oxazole and thiazole ring.
A among the group Z
2Base can be, for example, and-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6, R then
6Be selected from methyl or-CF
3And R
7, R
8And R
9Independently be selected from hydrogen or methyl.
In the group Z of the many embodiments of the present invention, x and y are 0, and A
2Be hydrogen, methyl ,-CN ,-OH or-COOH.
Group-C (=O) object lesson of Z comprises the following group that is selected from formula (C)-(P):
Wherein,
R
12Be selected from hydrogen ,-CH
3,-OH ,-CN or-COOH;
R
13Be selected from hydrogen ,-F ,-CF
3,-OCF
3,-Br ,-Cl ,-OCH
3,-CH
3,-CN or-COOH;
R
14Be selected from hydrogen ,-F ,-CF
3,-OCF
3,-Br ,-Cl ,-OCH
3,-CH
3,-CN ,-OH or-COOH;
R
15And R
16Independently be selected from hydrogen or (C
1-C
6) alkyl, perhaps R
15And R
16The ring amino that forms 4-7 annular atoms with their institute's bonded nitrogen-atoms encircles;
R
17Be selected from hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (=O)-, (C
1-C
6) alkyl SO
2-, benzyloxycarbonyl-or-C (=O) OCH
3
At present preferred group-C (=O) type of Z comprises that those are selected from down those groups of group:
(i) formula D, wherein, R
12Be hydrogen, R
14Be methyl, trifluoromethyl, trifluoromethoxy, 3-, 4-or 5-fluorine, 3-, 4-or 5-chlorine or 3-, 4-or 5-cyano group, or the 6-hydroxyl;
(ii) formula E, wherein, R
12Be hydrogen, R
14Be methyl, trifluoromethyl, 4-or 5-fluorine, 4-or 5-chlorine or 4-or 5-cyano group or 2-or 6-hydroxyl;
(iii) formula H;
(iv) formula (C) or (K)-(P) in arbitrary, wherein, R
12Be hydrogen, R
13Or R
14Be F, Cl, trifluoromethyl, trifluoromethoxy, cyano group, methyl sulphonyl
Present particularly preferred group-C (=O) type of Z has formula C, wherein, and R
12Be hydroxyl, cyano group or-COOH, R
13Be fluorine, methyl, trifluoromethyl, cyano group or methoxyl group.
When mentioning formula formula (C)-(P), any substituting group in the hetero-aromatic ring must meet known drug chemistry principle certainly.For example, any substituting group in the nitrogenous hetero-aromatic ring or CN can not be adjacent with nitrogen-atoms, therefore estimate that this substituting group can be used as good leavings group, these potentiality that just mean this in vivo compound and nucleophilic partial reaction are big, cause covalent linkage to form, this has been considered to genotoxic potential usually and has been out of favour.Also for example, might any OH substituting group will be adjacent with nitrogen-atoms so this compound will cause genotoxic potential.
A concrete subclass of The compounds of this invention is made of compound or its salt, hydrate, solvate, single enantiomorph or the N-oxide compound of formula (IA):
Wherein
A
1Be-COOH or tetrazyl;
-R
1-be-CH
2-,-CH (OH)-,-CHCH
3-,-CH
2O-
*, wherein, the key of representing with asterisk is connected in A
1
R
4, R
5, R
4' and R
5' independently be selected from hydrogen ,-F ,-CN or-Cl;
J is 1,2 or 3
Y is 0 or 1
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-;
A
4Be (i) optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocycle carbocyclic ring of one or more replacements, or
(ii) have 4-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocyclic heterocycles of one or more replacements.
In compound (IA), R
4Can be, for example, hydrogen, and R
5Can not hydrogen and be positioned at contraposition.Individually or with this characteristics combination, in compound (IA), R
4' can be, for example, hydrogen, and R
5' can not be hydrogen and be positioned at the ortho position.
Concrete The compounds of this invention comprises those among this paper embodiment.
The compounds of this invention acts on maincenter and periphery Cannabined receptor CB1.Some compounds are less to the effect of central nervous system, and promptly compound is not easy to cross over hemato encephalic barrier and related less with the side effect of central nervous system mediation.
The compounds of this invention is adjusted by the natural signals transduction function that suppresses Cannabined receptor CB1.Therefore this compound is CB1 receptor antagonist, inverse agonist or partial agonist.
Term " CB1 antagonist " or " Cannabined receptor CB1 antagonist " are meant with receptors bind or in its vicinity and lack the compound of any real ability of activated receptor itself.Therefore the CB1 antagonist can prevent or reduce CB1 agonist such as endogenous agonist N-arachidonic acyl glycollic amide (anandamide) to the functional activation of acceptor or occupy.This term is well known in the art.
Term " CB1 inverse agonist " or " Cannabined receptor CB1 inverse agonist " are meant bind receptor and demonstrate the compound of the pharmacotoxicological effect opposite with the CB1 receptor stimulant.Inverse agonist can effectively be resisted the acceptor that need not the part effect and have some type of intrinsic activity (being also referred to as ' constitutive activity ').This term is well known in the art.What this area was known equally is, this CB1 inverse agonist also is called the CB1 antagonist, and this general characteristic of two types is identical.Therefore, in literary composition of the present invention, term " CB1 antagonist " is understood to include " CB1 antagonist " defined above and " CB1 inverse agonist " usually.
Term " CB1 partial agonist " or " Cannabined receptor CB1 partial agonist " are meant the compound that acts on the acceptor identical with full agonist but produce more weak maximum pharmacological reaction and have low intrinsic activity level.This term is well known in the art.
According to preferred implementation of the present invention, " CB1 conditioning agent " or " Cannabined receptor CB1 conditioning agent " is CB1 antagonist or inverse agonist compound.
The compounds of this invention is used for the treatment of disease or the illness that is subjected to the active mediation of CB1 receptor signal transduction.The example of this disease and symptom and their methods of treatment are listed hereinbefore.Do not add restriction, they comprise fat and overweight, the prevention weight increase, treatment and fat direct or indirect relevant disease and symptom (metabolism syndrome for example, diabetes B, cardiovascular disorder, fat, metabolic function overweight or that normal type is individual is unusual, metabolic disease or metabolism disorder, cancer, hepatopathy and other secondary diseases above-mentioned), and treatment not necessarily with fat diseases associated and illness (eating disorder disease for example, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, the reproductive function obstacle, hepatopathy, fibrillation related disease and above-mentioned other clinical indications).They can be used for regulating mammiferous body weight and energy expenditure and are used to regulate the main ingredient that relates to metabolism syndrome, too much as stomach fat, cause atheromatous dyslipidemia (HDL-C, triglyceride level, LDL, apolipoprotein B, adiponectin horizontal abnormality), hypertension, hyperglycemia, hyperuricemia, non-alcoholic fatty liver disease/fatty degeneration of liver, liver transaminase, gamma-glutamyl-transferring enzyme and microalbuminuria raise.The compounds of this invention has different physicochemical properties and can be used for regulating periphery CB1 acceptor and maincenter CB1 acceptor in various degree.Those The compounds of this invention relevant with the CB1 acceptor there being low central action induce the tendency of neurological and neural system side effect to reduce.
The compounds of this invention can be used for the treatment of fat combination with other therapeutic agents, described therapeutical agent plays a role by different binding modes, as the central action to satiety or hungry signal, thirst for mechanism, appetite stimulator, Leptin/Regular Insulin/central nervous system approach, stomach and intestine-neural approach, metabolic rate, energy expenditure, ingestion of food, fat stores, fat is drained, digestive tract power, steatogenesis, glucose transport, glycogenolysis, sugar degraded, steatolysis or the like, comprise: monoamine energy conditioning agent (inhibitor, agonist, antagonist, analogue) (NA (norepinephrine), 5-HT (thrombotonin), DA (Dopamine HCL)) acceptor or transport molecule, neural ionic channel, Leptin or Leptin acceptor, Neuropeptide Y Receptors, PP (pancreatic polypeptide), PYY, protein Y Y3-36, ghrelin or ghrelin receptor, motilin or the motilin receptor, appetite peptide or orexin receptor, bombesin or bombesin-like peptide acceptor, somatostatin or the somatostatin receptor, MCHR
1(melanin concentration hormone acceptor 1), CNTF (ciliary neurotrophic factor), AgRP (wild grey associated protein), POMC (proopiomelanocortin), CART (Cocaine and Amphetamine are regulated transcript), α-MSH (alpha-melanophore-stimulation hormone), MC4 (melanocortin-4) or MC3 (melanocortin-3) acceptor, galanin receptors, Relaxin-3 acceptor, the GPR7 acceptor, GPR
119 acceptors, GPR
10 acceptor, neuromedin U acceptor, the free-fat acid acceptor, tethelin, Na Sifating (nesfatin)-1, Opioid Receptors, neuropeptide FF receptor, PTP-1B (tyrosine phosphatase), PPAR (Pexoxisome proliferator activated receptor) acceptor, retinoic acid receptor X heterodimer, adiponectin (being also referred to as Acrp30) (lipocyte complement related protein of 30kDa), fatty acid metabolism, H (histamine) acceptor, CCK-A (the or CCK-A acceptor of cholecystokinin-A), GLP-1 (glucagon-sample peptide-1) or GLP-1 acceptor, oxyntomodulin, adrenomedullin, DPP-IV (DPP IV), islet amyloid polypeptide, β-3-adrenergic receptor, UCP (uncoupling protein), thryoid receptor, Tiroidina-stimulation hormone receptor, 1 type 11beta-Hydroxysteroid dehydrogenase, amylase, DHEAS (dehydroepiandrosterone sulfate), CRH (corticotropin releasing hormone) or crh receptor, carboxypeptidase, lipid acid is synthetic, the HMG-CoA reductase enzyme, ileal bile acid transfer, gastrointestinal lipase, P57, AMP-activated protein kinase (AMPK).
The compounds of this invention can with the combination with other therapeutic agents that is used for the treatment of metabolism syndrome or obesity-related disease, described disease is as cardiovascular disorder (hypertension, congestive cardiomyopathy, varix, pulmonary infarction, coronary heart disease [CHD], liver cirrhosis), neurological disorder (apoplexy, the special property sent out intracranial hypertension, meralgia paraesthetica), respiratory illness's (expiratory dyspnea, obstructive sleep apnea, hypoventilation syndrome, pickwickian syndrome, asthma), musculoskeletal disease (motionless, degenerative osteoarthritis, lumbago and backache, osteoporosis), dermatosis (striae atrophicae or " stretch marks ", veins of lower extremity is retarded by silt, lymphedema, cellulitis, intertrigo, carbuncle, acanthosis, skin is superfluous), stomach and intestine (gastroesophageal reflux disease, non-alcoholic fatty liver disease/fatty liver, cholelithiasis, hernia, colorectal carcinoma), urogenital disease (stress incontinence, fat relevant glomerulopathy, mammary cancer and uterus carcinoma), psychological disease (depressed and low oneself respects, and quality of life is low), and endocrinopathy (metabolism syndrome, diabetes B, dyslipidemia, women's hyperandrogenism, polycystic ovarian syndrome, dysmenorrhoea, infertility, pregnancy complications, male hypogonadism).
When using The compounds of this invention, can suitably reduce picked-up of meals calorie and physical activity simultaneously.
Should be understood that the concrete dosage level to any particular patient will depend on various factors, comprising: the activity of the particular compound of employing, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, the seriousness of the drug regimen and the specified disease of receiving treatment.Optimal dose level and administration frequency will decide by the requirement of clinical trial and pharmacy field.Yet during to the human patients administration, the scope of the TDD of The compounds of this invention depends on mode of administration certainly usually between 1mg to 1000mg.For example, it is 10mg to 1000mg that oral administration may require TDD, and intravenously administrable only requires 1mg to 500mg.TDD can take single or broken dose to give, and can be according to doctor's decision outside the typical range that this paper provides.
These dosage are benchmark with average man's class object of the about 60-100kg of body weight.The doctor will determine the object of body weight outside this scope such as baby or the elderly, especially obese patient's dosage easily.
Can prepare the compound that the present invention relates to, be used for by any administration compatible with their pharmacokinetic property.The form of the composition of Orally-administrable can be tablet, capsule, pulvis, granule, lozenge, liquid preparation and gel preparation, such as oral, local or aseptic parenteral solution or suspension.The tablet and the capsule that are used for oral administration can be unit dosage, can contain conventional vehicle, and tackiness agent for example is such as syrup, gum arabic, gelatin, Sorbitol Powder, tragacanth gum or polyvinylpyrrolidone; Filler is such as lactose, sugar, W-Gum, calcium phosphate, Sorbitol Powder or glycine; The compressing tablet lubricant is such as Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent, such as yam starch, or acceptable wetting agent such as sodium lauryl sulphate.Can carry out dressing to tablet according to the method for knowing in the common pharmaceutical industry.The form of oral liquid can be for example water-based or oily suspensions, solution, emulsion, syrup or elixir, perhaps can show as drying products, and this product rebuilds with water or other suitable carriers before use.This class I liquid I preparation can contain conventional additive, and suspension agent for example is such as Sorbitol Powder, syrup, methylcellulose gum, glucose syrup, gelatin hydrogenant edible-fat; Emulsifying agent is such as Yelkin TTS, dehydrating sorbitol monooleate or gum arabic; Non-aqueous carrier (can comprise edible oil) is such as Prunus amygdalus oil, fractionated Oleum Cocois, grease such as glycerol, propylene glycol or ethanol; Sanitas, such as methyl p-hydroxybenzoate or propylparaben, or Sorbic Acid, and if necessary, conventional sweetener or tinting material.
Activeconstituents also can pass through parenteral admin in sterile media.According to carrier and the concentration used, medicine can suspend or be dissolved in the carrier.Advantageously, will be dissolved in the carrier as the adjuvant of local anesthetic, sanitas and buffer reagent and so on.
Synthetic
The synthetic of compound involved in the present invention (I) has multiple synthetic schemes, but all schemes all depend on the known chemistry of synthesis of organic scholar.Therefore, can come the compound of synthesis type (I) according to step that describe in the normative document and well-known to those skilled in the art.Typical literature reference is; " Advanced Organic Chemistry (Advanced organic chemistry) "; the 4th edition (Willie press (Wiley)); J March; " comprehensive organic transformation (Comprehensive Organic Transformation) "; the 2nd edition (Willie press); R.C.Larock; " heterocyclic chemistry handbook (Handbook of Heterocyclic Chemistry) "; the 2nd edition (Pa Jiameng press); A.R. block emerald green this base (A.R.Katritzky)); P.G.M. 5 (P.G.M.Wuts) and T.W. Green Buddhist nuns (T.W.Greene) " organic chemistry protecting group " (Greene ' s Protective Groups in OrganicChemistry) now; the 4th edition (Willie press); for example at " Synthesis "; " Acc.Chem.Res. "; the survey article that finds in " Chem.Rev "; perhaps can be by the main literature resource of online normative document search identification, or as the less important resource of " Chemical Abstracts (chemical abstracts) " or " Beilstein " and so on.
General route of synthesis
The approach of listing does not below constitute exhaustive.
The example condition that provides represents that a class and those normative documents that can mention find in originating in the above.Information of mentioning in the concrete bibliography of quoting and condition can be in addition/do not add modification/optimization to be used further to given material.
Can be with-N (R
3) R
2-A
2Thereby part is introduced the compound that the protection form of corresponding carboxylic acid or described carboxylic acid obtains formula I, as described in following scheme:
Scheme 1
Therefore, HN (R
3) R
2-A
2 *Part contains nucleophilic nitrogen center and remainder can comprise final substituting group, substituent protection form (for example ester) or adopt the known standard procedure of those skilled in the art can change final substituent group (for example changing nitrile into tetrazolium) into.Therefore, the compound of formula I can directly obtain or obtain afterwards in standard conversion (as removing protecting group) according to scheme 1.
Carboxylic acid can be taked activated form (for example chloride of acid or active ester), perhaps can adopt suitable coupling agents such as dicyclohexylcarbodiimide (DCC) and promotor such as I-hydroxybenzotriazole (HOBT) directly to prepare from acid.
The compound of formula (I) also can obtain according to the correlated process of said process, and carboxylic acid derivative wherein (for example nitrile, ester or acid amides) or other appropriate precursors are changed into group A after forming acid amides
1The process of listing in for example following scheme:
Scheme 2
This process can comprise, for example, itrile group is transformed into tetrazolium (for example handling with sodiumazide and weak acid example hydrochloric acid dimethylamine) under standard conditions or itrile group is transformed into carboxylic acid in polar solvent such as DMF.A kind of conversion in back can directly realize (for example in hydrolysis under acidity or the alkaline condition) or realize in two step process, comprises forming ester or imines ester (imidate) (for example handling with ethanol and anhydrous hydrogen chloride) hydrolysis under standard conditions then (for example using aqueous sodium hydroxide solution) earlier.
The another kind of strategy of the compound of preparation formula (1) can be by A is introduced in suitable nucleophilic center alkylation
1Part.Therefore possible process can comprise those that list in the following scheme:
Therefore, R
1 *Part contains nucleophilic Sauerstoffatom, sulphur atom, nitrogen-atoms or carbon atom, the leavings group (for example bromine) that the X representative is suitable, and group A
1 *Can represent final substituting group or final substituent precursor such as itrile group or ester group.
Said process can be used for the compound of synthesis type (1), thus residue R
1, R
2And R
3In one or more side chains that comprise, perhaps R
2And R
3Form ring together.Perhaps, can obtain these compounds from correlated branch derivative or its precursor of formula (1).For example make R at suitable reactive site
1, R
2Or R
3One or more and alkylating agent (for example methyl iodide) reaction in the part.For example the compound of formula (1) can be by becoming itrile group to obtain alpha-alkylization (alkylation alpha-), as described in following scheme:
Scheme 4
For example, can when having suitable cofactor (for example TMEDA), in aprotic solvent (for example THF), adopt highly basic such as lithium diisopropylamine (LDA) to realize this conversion according to the process that those skilled in the art know.Thereby therefore can itrile group be changed into the compound of tetrazolium or carboxylic acid acquisition formula (1) according to the process of describing before.
Perhaps, can adopt functional group's change to obtain the compound of formula (1) from the compound of other formulas (1) as final step.For example, substituent R
4And R
5Can be introduced into phenyl ring or A in terminal stage
3Part, shown in following scheme:
Scheme 5
For example, this can be included in and bromizate the reaction of compound and zinc cyanide when having metal catalyst such as palladium (0) complex compound to obtain wherein R
4It is the compound of the formula (1) of cyano group.
This conversion also can be carried out on the intermediate of the compound that can change accepted way of doing sth I or in the protection of intermediate in form.Similarly, substituting group also can be introduced R in the terminal stage of reaction process
2Part.
The reactant that is used for such scheme can be described in document or the similar procedure by the described process of document obtains, and can transform the back by the simple functional group that those skilled in the art are familiar with under the certain situation and obtain.
Embodiment partly comprises the embodiment of different route of synthesis, the compound that the process that those skilled in the art find in can utilizing in the literary composition takes similar approach to come preparation formula I to represent.
Analyze:
1H NMR resonance is measured on Bruker Avance AMX 300MHz spectrometer, and the chemical shift of selected compounds is the downfield with respect to interior mark tetramethyl-silicomethane, with 1,000,000/(ppm) expressions.
Lcms analysis adopts following standard conditions to obtain:
Post; Gemini C18,5 μ m, 2.0 * 50mm.Flow velocity: 1.2 ml/min; Gradient: the acetonitrile of 0.1% trifluoroacetic acid aqueous solution preparation: the 10%-95% acetonitrile, 3.5 minutes, 95% acetonitrile was 1.0 minutes then.Instrument: Agilent 1100HPLC/MSD system, 254nm UV detects.MS-ionization pattern: API-ES (plus or minus).
The data of all compounds retention time (RT) and molion (M+H)
+Or (M-H)
-Expression.
UPLC/MS adopts following standard conditions to carry out on Waters Acquity
Post: ACQUITY UPLC BEH C18,1.7 μ m, 2.1 * 50mm.Flow velocity: 0.5 ml/min.Gradient: 0.1-1.0 minute: 24-94% acetonitrile solution, 1-1.8 minute: 94% acetonitrile.Properties-correcting agent: 0.1%HCOOH.MS-ionization pattern: API-ES (plus or minus ionization)
Preparation HPLC:
Under following standard conditions, instruct fraction collector (mass-directed fraction collection) to carry out with quality:
Post: YMC 19 * 100mm; Flow velocity: 20 ml/min.Gradient: 0-8 minute: the 10-70%MeCN aqueous solution, 8-9 minute: the 70-95%MeCN aqueous solution, 9-12 minute: 95%MeCN.Properties-correcting agent: 0.1%TFA; MS-ionization pattern: API-ES (just)
Synthesizing of intermediate:
The intermediate of formula [A], [B] and [C] prepares according to the description of following scheme:
Scheme 6
The pyrazole derivatives of formula [A] can obtain by well-known process (J.Med.Chem, 1999,42,769-776).
The intermediate of formula [B] is to obtain from the compound of formula [A], method is to have catalytic amount 2, during the carbon tetrachloride solution of 2 '-Diisopropyl azodicarboxylate (AIBN) with N-bromosuccinimide (NBS) bromination, then with aqueous ethanolic solution in the potassium cyanide reaction, then with aqueous sodium hydroxide solution with the ester hydrolysis.
The intermediate of formula [C] is from the intermediate of corresponding formula [B] and amine R
3R
4NH obtains by coupling, and can adopt 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC) and I-hydroxybenzotriazole (HOBT), or form chloride of acid in advance with oxalyl chloride, and catalytic amount N, dinethylformamide (DMF).
The intermediate of formula [D] and [E] is according to the description of following scheme preparation:
Scheme 7
The 4-acetoxyl group pyrazole derivatives of formula [D] can obtain (WO 2006035310) by well-known process.As mentioned above with amine R
3R
4The NH coupling then under standard conditions hydrolysis obtain the intermediate of formula [E].
Formula [A]
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid, ethyl ester [A1]
Under nitrogen with 4 '-chlorophenyl acetone (33.7g, heptane 200mmol) (340ml) solution adds two (trimethyl silyl) acid amides lithium (the 1M hexane solutions that stir, 240ml, 240mol) solution, stir speed (S.S.) is to make internal temperature be no more than 25 ℃ speed.(29.9ml 220mmol) and with mixture stirred 16 hours at 25 ℃ again to add diethyl oxalate after 2 hours.
With the gained solid filtering, to obtain (Z)-4-(4-chloro-phenyl)-2-hydroxy-3-methyl-4-oxo-but-2-ene acetoacetic ester lithium salts (76g), it is solid (76g) with heptane wash and vacuum section drying.
This solid (38g) is dissolved in acetate (350ml) and add 2-chlorophenyl hydrazine hydrochloride (16.11g, 90mmol).The mixture stirring at room was poured in the water (680ml) in 3 hours then, stirred after 2 hours with the collection of gained solid by filtration and by the pumping unit drying.Solid is dissolved in acetate (230ml) and with vlil 18 hours, is cooled to room temperature and pours in the water (600ml).Stir after 24 hours the gained precipitation is collected by filtering, wash with water, pass through from 2-propanol/water recrystallization purifying then.With the gained solid 50 ℃ of vacuum-dryings to obtain title compound [A1] (16.1g, 48%).
1H?NMR(CDCl
3)：δ1.44(3H，t)，2.36(3H，s)，4.48(2H，q)，7.09-7.12(2H，m)，7.28-7.35(6H，m)。
LCMS:RT=3.3 minute, (M+H)
+=375.
Formula [B]
5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-cyano methyl-1H-pyrazoles-3-carboxylic acid [B1]:
With 2,2 '-Diisopropyl azodicarboxylate (0.35g, 2.13mmol) [A1] that add to stir (16g, 42.6mmol) and N-bromosuccinimide (8.35g, 46.9mmol) tetracol phenixin (160ml) solution and mixture heating up refluxed 2 hours, be cooled to room temperature then.Add the saturated sodium metabisulfite aqueous solution (30ml) and mixture was stirred 24 hours, water (160ml) adds salt solution (40ml) dilution and extracts with ethyl acetate (240ml) then.Organic extract is with 1M sodium hydroxide solution (100ml) extraction, with anhydrous magnesium sulfate drying and vacuum-evaporation.
Resistates is dissolved in ethanol (100ml) and adds potassium cyanide (8.33g, water 127.8mmol) (25ml) solution.Mixture heating up was refluxed 16 hours.Add 2M sodium hydroxide solution (20ml) and continue and refluxed 30 minutes.
Mixture dilute with water (300ml) is also used ethyl acetate extraction (2 * 300ml) with the 2M hcl acidifying.The organic extract that merges filters with dried over mgso and by Celite pad, washs with the ethyl acetate solution of 1% acetate then with the ethyl acetate washing earlier.With filtrate vacuum-evaporation, then with resistates and toluene coevaporation to remove acetate and to obtain spumescence title compound [B1] (14.7g, 93%).
1H?NMR(DMSO-D
6)：δ3.91(2H，s)，7.10(2H，d)，7.23-7.37(6H，m)。
LCMS:RT=2.476 minute, (M+H)
+=372.
Formula [C1]
[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-(4-phenyl-Piperazine-1-carbonyl)-1H-pyrazoles-4-yl]-acetonitrile
[C1]:
Under the room temperature argon gas with EDAC (195mg, 1.00mmol) [B1] that add to stir (250mg, 0.7mmol) and HOBT (133mg, methylene dichloride 0.8mmol) (40ml) solution.(155mg 0.9mmol) also continues to stir 16 hours to add 2-(piperazinyl) pyrimidine after 15 minutes.Mixture is used the salt water washing then with saturated sodium bicarbonate aqueous solution washing (3x), uses dried over mgso, and filtering also, vacuum-evaporation obtains 9mg[C1 to obtain thick material by the thick material of preparation type chromatography purification].
LCMS:RT=3.450 minute.(M+H)
+＝519.0
Intermediate with following formula [C] also prepares from [B1] and corresponding amine according to above-mentioned similar approach:
Formula [D]
4-acetoxyl group-5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-1H-pyrazoles-3-carboxylic acid [D1]:
According to process (WO 2006035310) preparation of announcing.
1H?NMR(DMSO-D
6)：δ2.27(3H，s)，7.20(2H，d)，7.44(2H，d)，7.59(3H，m)，7.80(1H，d)，13.28(1H，s，br)。
Formula [E]
5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-hydroxyl-1H-pyrazoles-3-carboxylic acid 4-fluoro-Phenylpiperidine acid amides
[E1]:
According to the process of above in the preparation of [C1], listing with acid [D1] and the coupling of 4-fluorophenyl piperidines to obtain acetate 5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-(4-fluoro-benzyl carbamyl)-1H-pyrazoles-4-base ethyl ester.
(95mg 0.17mmol) is dissolved in hot methanol with this ester.(26mg is 0.19mmol) obtaining clarifying yellow solution, with this solution stirring at room 1 hour for disposable adding salt of wormwood.Reaction mixture 1M hcl acidifying, dilute with water is also used twice of dichloromethane extraction.Organic phase is merged, use anhydrous magnesium sulfate drying, filter also vacuum-evaporation to obtain faint yellow solid shape title compound [E1] (85mg, 96%).LCMS:RT=3.9 minute.(M+H)
+＝510.1
The compound of general formula [1]
Synthetic:
Compound [1.2]
The process of listing according to following scheme prepares:
Scheme 8
(0.36ml 2.8mmol) adds [C1] (0.10g, ethanol 0.19mmol) (1.5ml) suspension that stirs with the chlorine trimethyl silyl under the room temperature nitrogen.Mixture is cooled to room temperature and vacuum evaporating solvent 60 ℃ of heated overnight.In rough ester, added tetrahydrofuran (THF)/water (1: 1,6ml) Pei Zhi lithium hydroxide monohydrate (23mg, 0.6mmol) and stirring at room 16 hours, add the 1M hcl acidifying then, leach sedimentary compound and be further purified to obtain title compound [1.2] (10mg) by preparation HPLC.
Compound [1.1] is to adopt (note: first stage in this conversion is dewatered [C2]) for preparing with [C2] described similar process.
Compound [1.3]
The process of listing according to following scheme prepares:
[E1] (85mg, add in acetone 0.166mmol) (0.5ml) solution salt of wormwood (46mg, 0.33mmol) and the 2 bromopropionic acid ethyl ester (20.3ul, 0.183mmol).Gained suspension stirred overnight at room temperature is distributed between methylene dichloride and salt solution then.The organic phase anhydrous magnesium sulfate drying filters and vacuum-evaporation.Resistates is by silicon-dioxide column chromatography purification (2g), with methylene dichloride then ethyl acetate/heptane (1: 1) wash-out to obtain thickness gelationus { 5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-[4-(4-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-base oxygen base }-ethyl acetate (77mg, 78%).
LCMS:RT=35 minute.[M+H]
+＝596.1
(77mg, 0.129mmol) (22mg, mixture 0.51mmol) is stirred overnight at room temperature in tetrahydrofuran (THF)/water (2ml) with lithium hydroxide with this ester.The vacuum-evaporation tetrahydrofuran (THF).Water 1M hcl acidifying is saturated and use dichloromethane extraction with sodium-chlor.Make organic phase by be separated filter and vacuum evaporated solution to obtain thick material, by this thick material of preparation type chromatography purification [1.3] (46mg, 0.087mmol, 94%) to obtain white solid.
Compound [1.13]
In ethanol (300mL) solution of nitrile (35g), add sodium hydroxide (23g) and mixture heating up refluxed and spend the night.Leach white disodium salt precipitation after the cooling, use ethanol (50mL) washed twice, and spend the night at the vacuum drier inner drying.Then solid is added in the 500mL water and with 4N HCl acidifying, solid product is leached and vacuum drier inner drying 72 hours to obtain 36g diacid [F1].In toluene (300mL) solution of this product, add pyridine (2.2mL) and diacetyl oxide (15.6mL) and the reactant room temperature stirred and spend the night.Add again pyridine (1mL) and diacetyl oxide (10mL) and with the reactant room temperature stir 2 hours then 50 ℃ stirred 45 minutes.Add ethanol (150mL) then and the reactant room temperature stirred 48 hours, vacuum concentration and with resistates from the ethyl alcohol recrystallization purifying to obtain monoesters [F2] (15.6g).
In monoesters [F2] methylene dichloride (2mL) solution (0.3g), add oxalyl chloride (0.13mL) and DMF (1) under the ice bath temperature, reactant was stirred 30 minutes and stirring at room 2 hours under this temperature.In resistates, add methylene dichloride (2mL) behind the vacuum concentration and cool off reactant with ice bath.Add DIPEA (0.46mL) and 4-(3-fluorophenyl)-piperidine hydrochlorate (0.17g), reactant stirred spend the night, concentrated and by chromatography purification to obtain amide product (0.4g).Lithium hydroxide (0.1g) hydrolysis among this product water (1.5mL) and the THF (2mL), vacuum concentration and by from ethyl acetate and heptane recrystallization purifying to obtain [1.19], it is white solid (0.13g)
Compound [1.4]-[1.58] are to adopt with [1.13] similar mode to prepare from [F2] with corresponding primary amines or secondary amine.
Compound [1.52]
In the solution of LDA under-78 ℃ in 3mL THF (0.86mmol) among the adding 1mL THF 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(3-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-ethyl acetate (500mg, 0.58mmol, description preparation according to [1.13] step 4), and with reactant under this temperature, stirred 20 minutes.(0.27mL 4.3mmol) also made reactant be warming up to-10 ℃ with 5 hours to methyl iodide among the adding 5ml THF, added 0.5mL ammonium chloride then.With the reactant filtration under diminished pressure and by the preparation HPLC purifying to obtain ethyl ester (127mg, LCMS RT=3.6 minute.[M+H]
+＝594.1)。Add the lithium hydroxide (100mg) of THF/ water mixture preparation in 1: 1 and reaction mixture stirred 24 hours, the partial concentration that reduces pressure then and by preparation type chromatography purification to obtain title compound.
Compound [1.65]
In LDA under-45 ℃ in 5mL THF (0.46mmol) solution among the adding 1mL THF 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(3-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-ethyl acetate (0.58mmol, according to the description of [1.13] step 4 preparation), and reactant stirred 20 minutes holding under the temperature.(0.12g 0.46mmol), makes reactant be warming up to-10 ℃ with 5 hours, adds 0.5mL ammonium chloride then to add 2-benzene sulfonyl-3-oxa-aziridine (2-benzene sulfonyl-3-oxaziridine) among the 1ml THF.With reactant concentrating under reduced pressure, adding ethyl acetate (20mL), organic phase water (4mL) washing also concentrates to obtain rough ester.(LCMS RT=3.6 minute.[M+H]
+＝596.1)。
Add the lithium hydroxide (100mg) of THF/ water mixture preparation in 1: 1 and reaction mixture stirred 24 hours, the partial concentration that reduces pressure then, and by preparation type chromatography purification to obtain title compound.
The compound of general formula [2]
1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carbonyl]-4-phenyl-piperidines-4-carboxylic acid
[2.1]
The process of listing according to following scheme prepares:
Scheme 9
Process hydrolysis ester cpds [A1] according to synthetic [1.1] last step.According to the process of synthetic [C1] with gained acid and 4-phenyl-piperidines-4-carboxylic acid, ethyl ester coupling to obtain 1-[1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carbonyl]-4-phenyl-piperidines-4-carboxylic acid, ethyl ester.
LCMS:RT=3.525 minute.(M+H)
+＝548.1
(49mg adds lithium hydroxide monohydrate (25mg, water 0.6mmol) (0.5ml) solution in tetrahydrofuran (THF) 0.089mmol) (0.5ml) solution at the previous step products therefrom that stirs.Add 3% hydrochloric acid after 2 days to obtain the solution of pH2, (10ml) extracts this solution with methylene dichloride.Anhydrous magnesium sulfate drying is used in organic extract salt water washing, filters and vacuum-evaporation.Resistates is by the silicon-dioxide column chromatography purification, with ethyl acetate/heptane (9: 1) wash-out to obtain title compound [2.1] (14mg, 0.026mmol, 29%).
Obtain the analytical pure sample by preparation HPLC this material of purifying under standard conditions.
LCMS:RT=2.940 minute.(M+H)
+＝534.1
1H?NMR(DMSO-D
6)：δ2.10(2H，t，br)，2.08(3H，s)，2.44(2H，d，br)，3.11(1H，t，br)，3.37(1H，t，br)，4.18(1H，d，br)，4.38(1H，d，br)，7.22(2H，d)，7.27(1H，d)，7.35(2H，t)，7.40-7.47(5H，m)，7.50(1H，dd)，7.55-7.60(2H，m)。
The compound of general formula [3]
Synthetic:
Compound [3.1]
The process of listing according to following scheme prepares:
Scheme 10
With sodiumazide (28mg, 0.24mmol) and the Dimethyl Ammonium hydrochloride (100mg, 1.22mmol) add [C3] (40mg, N 0.08mmol), dinethylformamide (1ml) solution and with mixture 120 ℃ of heating 12 hours.Mixture is cooled to room temperature, adds entry (2mL) and isopropanol, also use ethyl acetate extraction, dry and vacuum concentration with 3% hydrochloric acid (10ml) acidifying with dissolving.Raw product by from the ethyl acetate/heptane recrystallization purifying to obtain title compound [3.1] (2.4mg, 5.5%).
Compound [3.2]-[3.4] are by preparing from intermediate [C2], [C4] and [C5] respectively with [3.1] described similar procedure.
The intermediate of formula [C] is from the intermediate of corresponding formula [B] and amine R
3R
4NH obtains by coupling, and can adopt 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC) and I-hydroxybenzotriazole (HOBT), or form chloride of acid in advance with oxalyl chloride, and catalytic amount N, dinethylformamide.
The compound of general formula [4]
Adopt as listed in scheme (6) and the scheme (10) and compound [3.1] (being used for [4.1] and [4.3]) and [1.13] (being used for [4.2] and [4.4]) described identical process prepare through intermediate [A2].
[A2] adopts the mode that is similar to intermediate [A1] to prepare, but replaces the 2-chlorophenyl hydrazine with 2-fluorobenzene hydrazine
Biological data:
Detection compound in following function Cannabined receptor-1 test, and estimate the IC of their antagonism CB1 receptor stimulants
50Value.
Compound [1.1], [1.3], [1.4], [1.5], [1.6], [1.7], [1.10], [1.11], [1.12], [1.13], [1.14], [1.15], [1.17], [1.19], [1.21], [1.23], [1.24], [1.25], [1.26], [1.27], [1.28], [1.29], [1.31], [1.33], [1.34], [1.35], [1.36], [1.37], [1.38], [1.39], [1.40], [1.42], [1.43], [1.45], [1.49], [1.50], [1.51], [1.52], [1.53], [1.54], [1.55], [1.56], [1.58], [1.59], [1.60], [1.61], [1.62], [1.63], [1.64], [1.65], [2.1], [3.2], [3.3], [3.4]], [3.5], [3.6], [3.7], [3.8], [3.9], [4.1], [4.2], [4.3], [4.4] IC
50Value is lower than 0.30 μ M.
The IC of compound [1.2], [1.9], [1.16], [1.18], [1.20], [1.22], [1.32], [1.41], [1.44], [1.46], [1.47], [3.1], [1.57]
50Value is between 0.3 μ M and 3.0 μ M
The IC of compound [1.8], [1.30], [1.48]
50Value is between 3.0 μ M and 10 μ M.
Biological assessment
Transfection and cell cultures-be cloned into carrier for expression of eukaryon pcDNA3.1 (because of dimension Qu Gen company (Invitrogen)) from the cDNA of human fat tissue cDNA library clone coding people CB1 (Cannabined receptor-1) acceptor (GenBank accession number NM_016083) and with it.
Produce the Chinese hamster ovary cell of stably express recombinant human CB1 with the plasmid that contains people CB1 receptor coding sequence in fat transfection amine (lipofectamin) the transfection Chinese hamster ovary cell (CHO-K1) according to the explanation of manufacturers.When having 600 μ g/ml G418 (Life Technologies Corporation (Life technology)), select resistance clone.The CHO-K1 cell of stable transfection is maintained at and is added with 10% foetal calf serum (because of dimension Qu Gen company), the Ham ' s F-12 substratum of 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates (Life Technologies Corporation) and 600 μ g/ml G418 (because of dimension Qu Gen company).
Cannabined receptor-1 functional trial.
At the functionally active of the foregoing description of in-vitro evaluation The compounds of this invention, by measure their suppress CP55940-inductive [
35S] GTP γ S estimates in conjunction with the ability of the film for preparing from the CHO-K1 cell of expressing human CB1 acceptor (describing " transfection and cell cultures ").CP55940 is a kind of non-selective CB1 that knows and CB2 receptor stimulant (Felder etc. for example, 1995, Molecular Pharmacology, (48) 443-50).Prepare film by standard procedure.In brief, with 10mM EDTA harvested cell and by centrifugal collection.With Ultra Turrax Homogenizer homogeneous cell mass in ice-cold 20mM Hepes (pH 7.4), 10mMEDTA and proteinase inhibitor (adequate proteins enzyme inhibitors mixing tab, Luo Shi (Roche)).Homogenate 4 ℃ with 14000rpm centrifugal 45 minutes.Be resuspended in the gained cell mass identical but only contain the damping fluid of 0.1mM EDTA and at 4 ℃ of centrifugal 45 minutes of 14 000rpm once more.Gained cell mass (film) is resuspended in 20mM Hepes (pH 7.4), 0.1mM EDTA, 2mM MgCl
2With proteinase inhibitor, and by the explanation mensuration protein concn of little BCA protein determination kit (Micro BCA Protein Assay Reagent Kit) (Pierre Si biotech company (Pierce Biotechnology)) according to manufacturers.Carry out [
35S] GTP γ S SPA (scintillation proximity assay) in conjunction with the test, in 96 hole titer plate when having 3nMCP55940 and various concentration determination compound with 5 μ g/ hole hCB1-film and 1nM[
35S] GTP γ S (PE company (Perkin Elmer)-NEG 030H) together room temperature cultivated 1 hour.Add 0.4mg/ hole SPA pearl (PVT-WGA then; The RPNQ0001 husky biopharmaceutical company (Amersham PharmaciaBiotech) of liking to be beautiful) and on the orbital oscillation device, continue to cultivate 30 minutes.The test damping fluid contains 50mM HEPES (pH 7.5), 50mM NaCl, 2.5mM MgCl
2, 0.1%BSA, 1 μ M GDP and 100 μ g/ml saponin(es.Also used Topcounter (PE Life Technologies Corporation (PerkinElmer Life Sciences)) to read radioactivity in centrifugal 5 minutes immediately titer plate 1500rpm.Data are analyzed and adopted Prism software (San Diego GP software company (GraphPad Software, San Diego)) to calculate the IC50 value by non-linear regression.
The body inner model of the influence that mensuration is crossed gastrointestinal smoother
Come the interior effect of body (heavy 20-30g during on-test, the maximum range of each experiment is 5g) of evaluation test compound by the antagonistic action that detects CB1 (Cannabined receptor 1) agonist R-(+)-influence that 55,212 pairs of male NMRI mouse gastrointestinal smoothers of WIN are crossed.This method as solicit guests or diners this (Lacroix) and hometown Lame (Guillaume) as described in (" newly organized pharmacological experiment guide " (Current Protocols in Pharmacology), Willie press, New York, 5.3.1.-5.3.8., 1998).
Known CB1 is subjected to the gastrointestinal smoother mistake of physical efficiency control rodents.Use the CB1 agonist, as R-(+)-WIN55,212 stimulations can reduce gi tract by the time, and CB1 antagonist (as Rimonabant) can be blocked this effect.The time of passing through that R-(+)-WIN 55,212 handles the mouse of back genetic defect CB1 acceptor does not change.Also show, give the CB1 antagonist separately and the influence opposite can occur with the CB1 agonist; Can increase the time of passing through.(Ai Zuo (Izzo) etc. for example, European Journal of Pharmacology, 384 (1999): 37-42 and OK a karaoke club (Carai) etc., British Journal of Pharmacology (2006): 1-8).Scientific and technical literature prompting, the effect of CB1 agonist and antagonist mainly (for example block Soviet Union (Casu) etc., European Journal of Pharmacology, 459 (2003): 97-105) by the periphery CB1 in the enteron aisle is receptor-mediated.
Described model is widely used in the body of CB1 antagonist qualitative.Rimonabant (the clinical activity agent that treatment is fat) has demonstrated tangible dose-dependent effect in model, further support this model to be fit to be used for measuring the interior effect of body of CB1 acceptor.
Animal maintains the normal phase of 12 hours cycle light and dark.Food (the solid type food of standard) and water arbitrarily provide except as otherwise noted.Test compounds is dissolved in carrier 1:5%N methyl-2-pyrrolidone (Sigma company (Sigma)) and 10%Solutol, and (giving volume is 5ml/kg for HS-15, the BASF) aqueous solution and give (p.o.) by oral gavage.R-(+)-WIN 55,212 (Sigma company) is scattered in the 1%DMSO of distilled water preparation and 49.5%2-hydroxypropyl-beta-cyclodextrin (carrier 2) and intraperitoneal gives (i.p.), giving volume is 10ml/kg.7 mouse of each treatment group.
The beginning stomach and intestine by experiment after making one night of mouse fasting.Give mouse 10% activated carbon suspension (the 0.4ml/ mouse gives by oral gavage).With the solvent of 2.5% gum arabic as activated carbon.Small intestine between also taking out from the pylorus to the caecum by cervical dislocation execution animal after 20 minutes.The distance that the measuring mark thing covers also is expressed as the per-cent that accounts for the small intestine total length.
With the effect of R-(+)-WIN 55,212 (2.5mg/kg) one or many dose evaluation test compounds that p.o. gives in the time of 45 minutes before, R-(+)-WIN 55,212nd, what i.p. gave 30 minutes the time before giving activated carbon.
Fig. 1 has shown that i.p. gives the influence that CB1 agonist R-(+)-WIN 55,212 (2.5mg/kg) back is passed through stomach when being with or without with embodiment 1.34 (10mg/kg p.o.) or Rimonabant (3mg/kg p.o.) pre-treatment (45 minutes).
Claims (29)
1. the compound of formula (IB), or its salt, hydrate, solvate, single enantiomorph or N-oxide compound:
Wherein:
A
1Be hydrogen ,-COOH or tetrazyl;
P and q independently are 0 or 1;
A
3Be phenyl or cycloalkyl, arbitrary choosing wantonly by R
4And/or R
5Replace;
R
4And R
5Independently be-R
9,-CN ,-F ,-Cl ,-Br ,-OR
9,-NR
7R
8,-NR
7COR
6,-NR
7SO
2R
6,-COR
6,-SR
9,-SOR
9Or-SO
2R
6
R
6Be C
1-C
4Alkyl, cycloalkyl ,-CF
3Or-NR
7R
8
R
7And R
8Independent is hydrogen, C
1-C
4Alkyl or cycloalkyl;
R
9Be hydrogen, C
1-C
4Alkyl, cycloalkyl, fluorizated C wholly or in part
1-C
4Alkyl;
R
1Be
(i) key, or
(ii)-(CH
2)
aB
1(CH
2)
b-, wherein, a and b independently are 0,1,2 or 3, prerequisite is that a+b is not more than 4, and B
1Be-CO-,-O-,-S-,-SO-,-SO
2-,-CH
2-,-CHOH-or-NR
7-; Or
(iii) be selected from down the divalent radical of group :-C (R
10) (R
11)-
*,-C (R
10) (R
11)-O-
*,-C (R
10) (R
11) CH
2-
*,-C (R
10) (R
11) CH
2-O-
*,-CH
2C (R
10) (R
11)-
*,-CH
2C (R
10) (R
11)-O-
*,-CH
2-O-C (R
10) (R
11)-
*With-C (R
10) (R
11)-O-CH
2-
*, wherein, the key of representing with asterisk is connected in the pyrazoles ring;
R
10Be hydrogen, R
11Be (C
1-C
3) alkyl; Or R
10And R
11All be (C
1-C
3) alkyl; Or R
10And R
11Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring; With
Group-N (R
3) R
2-A
2Have formula (II), (III), (IV) or (V):
Wherein, x and y independently are 0 or 1, and k is 1 or 2, and j is 1,2,3 or 4.
B
3Be-C (R
13) (R
14)-,-O-or-NR
7-or arbitrary orientation-O-C (R
13) (R
14)-,-CH
2-C (R
13) (R
14)-;
B
4Be-C (R
13) (R
14)-,-CO-or-SO
2-;
A
2Be hydrogen ,-COOH, tetrazyl ,-CN ,-CF
3,-COR
6,-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6, prerequisite is A
1And A
2One of be-COOH or tetrazyl;
A
4Be optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the monocycle carbocyclic ring or the monocyclic heterocycles of one or more replacements;
Ring A be optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocycle carbocyclic ring or the monocyclic heterocycles of one or more replacements; With
R
13And R
14Independent is hydrogen or (C
1-C
3) alkyl; Or R
13And R
14All be (C
1-C
3) alkyl; Or R
13And R
14Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring.
2. compound as claimed in claim 1, wherein:
R
9Be hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkoxyl group (C
1-C
4Alkyl)-, cycloalkyl, fluorizated C wholly or in part
1-C
4Alkyl; With
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-.
3. the compound of formula (I), or its salt, hydrate, solvate, single enantiomorph or N-oxide compound:
Wherein:
A
1Be hydrogen ,-COOH or tetrazyl;
P and q independently are 0 or 1;
A
3Be phenyl or cycloalkyl, arbitrary choosing wantonly by R
4And/or R
5Replace;
R
4And R
5Independently be-R
9,-CN ,-F ,-Cl ,-Br ,-OR
9,-NR
7R
8,-NR
7COR
6,-NR
7SO
2R
6,-COR
6,-SR
9,-SOR
9, or-SO
2R
6
R
6Be C
1-C
4Alkyl, cycloalkyl ,-CF
3Or-NR
7R
8
R
7And R
8Independent is hydrogen, C
1-C
4Alkyl or cycloalkyl;
R
9Be hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkoxyl group (C
1-C
4Alkyl)-, cycloalkyl or fluorizated C wholly or in part
1-C
4Alkyl;
R
1Be
(i) key;
(ii) formula-(CH
2)
aB
1(CH
2)
b-divalent radical, wherein, a and b independently are 0,1,2 or 3, prerequisite is that a+b is 1,2 or 3, and B
1Be-CO-,-O-,-S-,-SO-,-SO
2-,-CH
2-,-CHCH
3-,-CHOH-or-NR
7-; Or
(iii) be selected from down the divalent radical of group :-C (R
10) (R
11)-
*,-C (R
10) (R
11)-O-
*,-C (R
10) (R
11) CH
2-
*,-C (R
10) (R
11) CH
2-O-
*,-CH
2C (R
10) (R
11)-
*,-CH
2C (R
10) (R
11)-O-
*,-CH
2-O-C (R
10) (R
11)-
*With-C (R
10) (R
11)-O-CH
2-
*, wherein, the key of representing with asterisk is connected in the pyrazoles ring;
Z is selected from morpholine-1-base and formula (II), (III), (IV) and group (V)
Wherein,
X and y independently are 0 or 1,
K is 1 or 2;
J is 1,2,3 or 4.
A
2Be hydrogen ,-COOH, tetrazyl ,-CN ,-CF
3,-COR
6,-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6, prerequisite is to work as A
1A when being hydrogen
2Be-COOH or tetrazyl,
A
4Be key, or
(i) have 3-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocycle carbocyclic ring of one or more replacements; Or
(ii) have 4-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocyclic heterocycles of one or more replacements,
The prerequisite of formula (IV) is to work as A
4When being key, B
3Be not connected in A by oxygen or nitrogen
4
B
3Be-C (R
13) (R
14)-,-O-or-NR
7-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14The prerequisite of)-, formula (II)-(V) is, when x is 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A then
2Be hydrogen;
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-;
Ring A is:
(a) have 3-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocycle carbocyclic ring of one or more replacements; Prerequisite be when A be not that aromatic series, x are 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A
2Be hydrogen; Or
(b) have 4-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8In the condensed monocyclic heterocycles of one or more replacements; Prerequisite be when A be not that aromatic series, x are 1 and B
3Be connected in A by oxygen or nitrogen
2The time, A
2Be hydrogen;
R
10Be hydrogen, R
11Be (C
1-C
3) alkyl or-OH; Or R
10And R
11All be (C
1-C
3) alkyl; Or R
10And R
11Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring; With
R
13And R
14Independent is hydrogen or (C
1-C
3) alkyl; Or R
13And R
14All be (C
1-C
3) alkyl; Or R
13And R
14Form (C with the carbon atom that they connected
3-C
5) cycloalkyl ring.
4. compound as claimed in claim 3, wherein, A
1Be-COOH or tetrazyl;
5. as claim 3 or the described compound of claim 4, wherein, R
1Base is-CH
2-,-CH
2O-
*, or-CH
2OCH
2-.
6. as each described compound among the claim 3-5, wherein, R
4Be hydrogen, R
5Not hydrogen and be positioned at-(CH
2) the q-contraposition.
7. as each described compound among the claim 3-6, wherein, R
4Be hydrogen, R
5Not hydrogen and be positioned at-(CH
2) the p-ortho position.
8. as each described compound among the claim 3-7, wherein, Z has following formula:
9. as each described compound among the claim 1-7, wherein, Z has following formula:
Wherein, the optional quilt-F of thick phenyl ring ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Replace.
10. as each described compound among the claim 3-8, wherein, B
3Be exist and be-C (R
13) (R
14)-or arbitrary orientation-O-C (R
13) (R
14)-,-CH
2-C (R
13) (R
14)-or-NR
7-, wherein, R
13And R
14Independent is hydrogen or methyl; R
7Be hydrogen, methyl or cyclopropyl;
11. as each described compound among the claim 3-8, wherein, B
4Be exist and be-C (R
13) (R
14)-, wherein, R
13And R
14Independent is hydrogen or methyl.
12. as each described compound among the claim 3-8,10 or 11, wherein, A
4Be exist and be selected from down group: phenyl, pyridine, pyrimidine, thiophene, furans, oxazole and thiazole ring.
13., wherein, work as A as each described compound among the claim 3-12
2Be-SO
2R
6,-OR
9,-NR
7R
8,-NR
7COR
6, or-NR
7SO
2R
6The time R
6Be selected from methyl or-CF
3R
7, R
8And R
9Independently be selected from hydrogen or methyl.
14. as each described compound in claim 1-9 or 12, wherein, in Z, x and y are 0, A
2Be hydrogen, methyl ,-CN ,-OH or-COOH.
15. as each described compound among the claim 1-7, wherein, group-C (=O) Z is selected from the group of formula (C)-(P):
Wherein,
R
12Be selected from hydrogen ,-CH
3,-OH ,-CN or-COOH;
R
13Be selected from hydrogen ,-F ,-CF
3,-OCF
3,-Br ,-Cl ,-OCH
3,-CH
3,-CN or-COOH;
R
14Be selected from hydrogen ,-F ,-CF
3,-OCF
3,-Br ,-Cl ,-OCH
3,-CH
3,-CN ,-OH or-COOH;
R
15And R
16Independently be selected from hydrogen or (C
1-C
6) alkyl, perhaps R
15And R
16The ring amino that forms 4-7 annular atoms with their institute's bonded nitrogen-atoms encircles;
R
17Be selected from hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkyl C (=O)-, (C
1-C
6) alkyl SO
2-, benzyloxycarbonyl-or-C (=O) OCH
3
16. compound as claimed in claim 15, wherein, group-C (=O) Z is selected from down group:
(i) formula D, wherein, R
12Be hydrogen, R
14Be methyl, trifluoromethyl, trifluoromethoxy, 3-, 4-or 5-fluorine, 3-, 4-or 5-chlorine or 3-, 4-or 5-cyano group, or the 6-hydroxyl;
(ii) formula E, wherein, R
12Be hydrogen, R
14Be methyl, trifluoromethyl, 4-or 5-fluorine, 4-or 5-chlorine or 4-or 5-cyano group or 2-or 6-hydroxyl;
(iii) formula H;
(iv) formula (C) or (K)-(P) in arbitrary, wherein, R
12Be hydrogen, R
13Or R
14Be F, Cl, trifluoromethyl, trifluoromethoxy, cyano group, methyl sulphonyl.
17. compound as claimed in claim 15, wherein, group-C (=O) Z has formula C, wherein, and R
12Be hydroxyl ,-CN or-COOH, R
13Be-F, methyl ,-CF
3,-CN or methoxyl group.
18. as each described compound among the claim 3-17, wherein, R
4And R
5Independently be selected from hydrogen ,-F ,-CN or-Cl.
19. compound or its salt, hydrate, solvate, single enantiomorph or the N-oxide compound with formula (IA) as claimed in claim 3:
Wherein
A
1Be-COOH or tetrazyl;
-R
1-be-CH
2-,-CH (OH)-,-CHCH
3-,-CH
2O-
*, wherein, the key of representing with asterisk is connected in A
1
R
4, R
5, R
4' and R
5' independently be selected from hydrogen ,-F ,-CN or-Cl;
J is 1,2 or 3
Y is 0 or 1
B
4Be-C (R
13) (R
14)-,-CO-,-SO
2-,-O-or arbitrary orientation-O-C (R
13) (R
14)-or-CH
2-C (R
13) (R
14)-;
A
4Be (i) optional quilt-F with 3-8 annular atoms ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocycle carbocyclic ring of one or more replacements, or
(ii) have 4-8 annular atoms optional quilt-F ,-Cl ,-Br ,-CN ,-CF
3, C
1-C
4Alkyl, cycloalkyl ,-OR
9, oxo or-NR
7R
8Or SO
2R
6In the monocyclic heterocycles of one or more replacements.
20. compound as claimed in claim 3, it is selected from down group:
5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-[4-(4-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(3,5-two chloro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(3-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
2-{1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-phenoxy group)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-propionic acid,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(3-cyano group-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[3-(4-trifluoromethyl-phenyl)-tetramethyleneimine-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(2-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(4-chloro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
2-{1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[4-(2-fluoro-phenyl)-piperidines-1-carbonyl]-1H-pyrazoles-4-yl }-propionic acid,
[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-(4 '-hydroxy-5-methyl base-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,4 '] bipyridyl-1 '-carbonyl)-1H-pyrazoles-4-yl]-acetate,
1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-3-[3-(4-fluoro-phenyl)-tetramethyleneimine-1-carbonyl]-1H-pyrazoles-4-yl }-acetate,
And their salt, hydrate and solvate.
21 1 kinds of pharmaceutical compositions, it contains as each described compound in the above-mentioned claim and one or more pharmaceutically acceptable carrier or vehicle.
22. be subjected to the disease of the active mediation of CB1 receptor signal transduction or the application in the illness in treatment as each described compound among the claim 1-20.
23. application as claimed in claim 22 is used for the treatment of obesity, overweight, treatment and fat and overweight directly or indirectly relevant disease and symptom.
24. application as claimed in claim 23, wherein, described and fat and overweight directly or indirectly relevant disease be metabolism syndrome, diabetes B, cardiovascular disorder, metabolic function unusually, metabolic disease or metabolism disorder or hepatopathy.
25. application as claimed in claim 22 is used for the treatment of eating disorder disease, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, reproductive function obstacle, hepatopathy or fibrillation related disease.
26. a treatment is subjected to the disease of the active mediation of CB1 receptor signal transduction or the method for illness, described method comprise the object significant quantity of suffering from this disease or illness as each described compound among the claim 1-20.
27. method as claimed in claim 26, be used for the treatment of fat, overweight, treatment and fat and overweight direct or indirect relevant disease and symptom, this method comprise the object significant quantity of suffering from this disease or illness as each described compound among the claim 1-20.
28. method as claimed in claim 27, wherein, described and fat and overweight directly or indirectly relevant disease be metabolism syndrome, diabetes B, cardiovascular disorder, metabolic function unusually, metabolic disease or metabolism disorder or hepatopathy.
29., be used for the treatment of eating disorder disease, addictive disorders, mental disorder, neurological disorder, sexual dysfunction, reproductive function obstacle, hepatopathy or fibrillation related disease as the method that claim 26 is stated.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0625197.9 | 2006-12-18 | ||
| GB0625197A GB0625197D0 (en) | 2006-12-18 | 2006-12-18 | Cannabinoid receptor modulators |
| GB0717998.9 | 2007-09-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101558058A true CN101558058A (en) | 2009-10-14 |
Family
ID=37712325
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800465651A Pending CN101568525A (en) | 2006-12-18 | 2007-12-17 | Cb1 receptor modulators |
| CNA2007800465454A Pending CN101558058A (en) | 2006-12-18 | 2007-12-17 | Modulators of CB1 receptors |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800465651A Pending CN101568525A (en) | 2006-12-18 | 2007-12-17 | Cb1 receptor modulators |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN101568525A (en) |
| GB (1) | GB0625197D0 (en) |
| ZA (1) | ZA200904663B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212058A (en) * | 2011-04-14 | 2011-10-12 | 范如霖 | Single composite medicament (chiral nitrogenous heterocyclic ester) and synthesis method thereof as well as application of chiral nitrogenous heterocyclic ester in preparing low-toxicity CB1 receptor inhibitor |
-
2006
- 2006-12-18 GB GB0625197A patent/GB0625197D0/en not_active Ceased
-
2007
- 2007-12-17 CN CNA2007800465651A patent/CN101568525A/en active Pending
- 2007-12-17 CN CNA2007800465454A patent/CN101558058A/en active Pending
-
2009
- 2009-07-02 ZA ZA200904663A patent/ZA200904663B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212058A (en) * | 2011-04-14 | 2011-10-12 | 范如霖 | Single composite medicament (chiral nitrogenous heterocyclic ester) and synthesis method thereof as well as application of chiral nitrogenous heterocyclic ester in preparing low-toxicity CB1 receptor inhibitor |
| CN102212058B (en) * | 2011-04-14 | 2014-04-02 | 范如霖 | Single composite medicament (chiral nitrogenous heterocyclic ester) and synthesis method thereof as well as application of chiral nitrogenous heterocyclic ester in preparing low-toxicity CB1 receptor inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200904663B (en) | 2010-05-26 |
| GB0625197D0 (en) | 2007-01-24 |
| CN101568525A (en) | 2009-10-28 |
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Application publication date: 20091014 |