CN101528684A - Biphenyl sulfonyl and phenyl-heteroaryl sulfonyl modulators of the histamine h3-receptor useful for the treatment of disorders related thereto - Google Patents
Biphenyl sulfonyl and phenyl-heteroaryl sulfonyl modulators of the histamine h3-receptor useful for the treatment of disorders related thereto Download PDFInfo
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- CN101528684A CN101528684A CNA2007800388068A CN200780038806A CN101528684A CN 101528684 A CN101528684 A CN 101528684A CN A2007800388068 A CNA2007800388068 A CN A2007800388068A CN 200780038806 A CN200780038806 A CN 200780038806A CN 101528684 A CN101528684 A CN 101528684A
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Abstract
The present invention relates to certain biphenyl sulfonamide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3- receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and the like.
Description
Technical field
The present invention relates to regulate some formula (Ia) compound and its medical composition of histamine H 3 receptor activity.Compound of the present invention and its medical composition are that described histamine H 3 associated conditions are for example cognitive disorder at the method that is applicable to treatment histamine H 3 associated conditions, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders (narcolepsy for example, the shift work syndromes, drowsiness as the pharmacological agent side effect, for auxiliary finishing the work kept alertness or the like, damping off, hypersomnia, the somnolence syndromes, jet lag, sleep apnea or the like), attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, last air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia, alzheimer's disease (Alzheimer ' s disease) or the like.
Background technology
Summary of the invention
An aspect of of the present present invention relates to some suc as formula the compound shown in (Ia):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
1Be selected from the group that forms by following each group: H, C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6Haloalkyl sulfenyl, C
3-C
7Heterocyclic radical, hydroxyl, mercaptan, nitro, phenyl and sulphonamide, and each group randomly replaces through 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through 1,2,3 or 4 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro, oxo base and sulphonamide are formed;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene, C
3-C
7Inferior heterocyclic radical or phenylene, each group randomly replaces through 1,2,3,4,5,6,7 or 8 substituting group, and described substituting group independently is selected from by C
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen, hydroxyl and oxo base are formed;
Ring A is the R that respectively hangs oneself
12, R
13, R
14And R
151 of replacement, 3-phenylene or 1,4-phenylene, wherein R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed; Or
Ring A is separately randomly through R
16, R
17And R
186 yuan of inferior heteroaryls or 5 yuan of inferior heteroaryls, wherein R of replacing
16, R
17And R
18Independently be selected from separately by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
2, R
3, R
4And R
5Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
6, R
7, R
8And R
9Independently be selected from by H, C separately
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen and hydroxyl are formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it;
Condition is:
1) ring B and R
1-W-S (O)
2The sulphur of-group not with the ring A the adjacent ring Atom Bonding; And
2) if ring A is 1,3-phenylene or 1, the 4-phenylene, and W is C
3-C
7Inferior heterocyclic radical is so with R
1-W-S (O)
2The annular atoms of the W of the direct bond of sulphur of-group is not a nitrogen.
An aspect of of the present present invention relates to medical composition, and it comprises The compounds of this invention and pharmaceutically acceptable supporting agent.
An aspect of of the present present invention relates to the method for the treatment of individual histamine H 3 receptor associated conditions, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the method for the treatment of the histamine H 3 receptor associated conditions, described illness be selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders (for example narcolepsy, damping off, hypersomnia, somnolence syndromes, jet lag, sleep apnea or the like), attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, go up the group that air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia and alzheimer's disease are formed.
An aspect of of the present present invention relates to the individual sleep and the method for Arousal disorders for the treatment of, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the method for the treatment of individual cognitive disorder, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the method that individuality is dampinged off for the treatment of, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the method for bringing out individual awakening, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the method for the treatment of individual pain, and it comprises to the individuality that needs are arranged throws and The compounds of this invention or its medical composition for the treatment of significant quantity.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine that supplies treatment histamine H 3 receptor associated conditions.
An aspect of of the present present invention relates to The compounds of this invention and is used to make purposes for the medicine of treatment histamine H 3 receptor associated conditions, described illness be selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders (for example narcolepsy, damping off, hypersomnia, somnolence syndromes, jet lag, sleep apnea or the like), attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, go up the group that air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia and alzheimer's disease are formed.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine that supplies treatment sleep and Arousal disorders.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine that supplies the treatment cognitive disorder.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine of dampinging off for treatment.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine that is used to bring out awakening.
An aspect of of the present present invention relates to the purposes that The compounds of this invention is used to make the medicine that supplies treatment pain.
An aspect of of the present present invention relates to the The compounds of this invention that uses for by the method for therapy for treating human body or animal body.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the histamine H 3 receptor associated conditions that passes through therapy for treating human body or animal body.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the histamine H 3 receptor associated conditions by therapy for treating human body or animal body, described illness be selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders (for example narcolepsy, damping off, hypersomnia, somnolence syndromes, jet lag, sleep apnea or the like), attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, go up the group that air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia and alzheimer's disease are formed.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the sleep of passing through therapy for treating human body or animal body or Arousal disorders.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the cognitive disorder that passes through therapy for treating human body or animal body.
An aspect of of the present present invention relates to the The compounds of this invention that uses for by the method for dampinging off of therapy for treating human body or animal body.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the awakening of bringing out human body or animal body by therapy.
An aspect of of the present present invention relates to the The compounds of this invention that uses for the method for the pain of passing through therapy for treating human body or animal body.
An aspect of of the present present invention relates to the preparation method for compositions, and it comprises The compounds of this invention is mixed with pharmaceutically acceptable supporting agent.
To proceed along with patent disclosure and illustrate these aspects and the others of present invention disclosed herein in more detail.
Description of drawings
Fig. 1 show by also synthetic (the R)-2-crassitude of L-dried meat ammonia alcohol with and be subsequently converted to (R)-1-(4-bromobenzene ethyl)-2-crassitude with (R)-the general synthesis flow of 4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide.
Fig. 2 shows the general synthesis flow for preparing The compounds of this invention by the microwave regulation and control type palladium catalysis suzuki reaction (Suzuki reaction) between phenyl-boron dihydroxide and the ring A through replacing such as leaving groups such as halogen or trifluoromethanesulfonic acid ester groups.The ring A that replaces through alkylsulfonyl is by thiol group and R
1-W-LG
4Reaction and the gained thioether further is oxidized to alkylsulfonyl and makes with the suitable oxidizing agent.Boric acid is to be prepared with two steps by the precursor that contains two leaving groups.The first step comprises with amine reacts.Second step comprised with boric acid three alkane esters reacts.
Fig. 3 shows the general synthesis flow for preparing The compounds of this invention by phenyl-halide or triflate or the like and the microwave regulation and control type palladium catalytic coupling reactions (for example suzuki reaction) between the ring A of sulfone and boric acid replacement.
Fig. 4 shows the general synthesis flow of preparation used intermediate in the preparation of The compounds of this invention.
Fig. 5 shows preparation The compounds of this invention (R wherein
8And R
9All be hydrogen) general synthesis flow.The first step is utilized formula R
1-W-LG
6Compound with to introducing R from the intermediate of Fig. 4
1-W-group.Second step comprised that replacing leaving group with amine (was LG
5).For (being R by selecting suitable reagent
1-W-LG
6) and introduce multiple R
1-W-group, this is the preparation that is particularly useful.This preparation also is applicable to by selecting suitable amine to introduce multiple R
10And R
11Group.
Fig. 6 shows the general synthesis flow of preparation used intermediate in the preparation of The compounds of this invention.
Fig. 7 shows preparation The compounds of this invention (R wherein
8And R
9All be hydrogen) general synthesis flow.For (being R by selecting suitable reagent
1-W-LG
6) and introduce multiple R
1-W-group, this is the preparation that is particularly useful.
Embodiment
Definition
For clarity and continuity purpose, will use to give a definition in the whole text at this patent file.
Term " agonist " plans that expression interacts with acceptor (for example histamine H 3 receptor) and activated receptor and cause the physiology of described acceptor or the part of pharmacological reaction feature.For instance, part with receptors bind after the activating cells internal reaction, or enhancing combines with the GTP of film.
Term " antagonist " plan to be illustrated in agonist (for example, endogenic ligand) identical site and receptor competition bonded part, but it does not activate the cell internal reaction by the acceptor initiation of activity form, thereby and can suppress agonist or the caused cell internal reaction of partial agonist.Antagonist does not weaken the baseline cell internal reaction under the situation that does not have agonist or partial agonist.
Term " contact " plans to be illustrated in ex vivo system or in vivo in the system specified portions to be gathered together.Therefore, histamine H 3 receptor and The compounds of this invention " are contacted " comprise to the individuality with histamine H 3 receptor (preferred human) and throw and The compounds of this invention, and (for example) introduced The compounds of this invention and contained cell preparation with histamine H 3 receptor or more in the sample of pure preparation.
Term " need treatment " and term " have needs " and are used interchangeably when treating to represent (for example, under the situation the mankind being doctor, nurse, nurse practitioner etc. by the paramedic mentioning; Under the animal situation of (comprising non-human mammal) for the animal doctor) done need treat the judgement that maybe will from treatment, benefit about individuality or animal.This judgement is made according to multiple factor, and described factor is in paramedic's areas of expertise, but it comprises about individuality or the animal understanding because of can be sick by disease, symptom or the illness of The compounds of this invention treatment or will be sick.Therefore, The compounds of this invention can protectiveness or preventative mode use; Or The compounds of this invention can be used for alleviating, suppresses or improves disease, symptom or illness.
Term " individuality " plans to represent any animal, comprises Mammals, preferred mouse, rat, other rodent, rabbit, dog, cat, pig, ox, sheep, horse or primate, and most preferably human.
The part of the acceptor of term " inverse agonist " plan expression and endogenous form or the receptors bind of composition activated form; and it suppresses to make it be lower than the normal primary activity level that is observed under the situation that does not have agonist or partial agonist by the baseline cell internal reaction of the acceptor initiation of activity form, or reduction combines with the GTP of film.Compare with the baseline response under the situation that does not have inverse agonist, exist baseline cell internal reaction under the situation of inverse agonist through suppressing preferably at least 30%, more preferably at least 50% and most preferably at least 75%.
The increase or the reduction of amount, quality, reaction or the effect of term " adjusting " plan expression given activity, function or molecule.
Term " medical composition " plan expression comprises at least a composition of active components that includes, but is not limited to salt, solvate and the hydrate of The compounds of this invention; Described thus composition is applicable to the appointment effective result of research in Mammals (for example (being not limited to) mankind).One of ordinary skill in the art will understand and understand the needs that are applicable to according to the technician and measure the technology whether activeconstituents has required effective result.
Term " treatment significant quantity " plans to be illustrated in to cause biology or the active compound of medical response or the amount of being sought by researchist, animal doctor, doctor or other clinician of medical agent among tissue, system, animal, individuality or the mankind that described biology or medical response comprise one or more in the following situation:
(1) preventing disease; For instance, to may tend to be attacked by a disease, symptom or illness but do not experience as yet or show that the pathology of described disease or the individuality of symptom carry out the prevention of disease, symptom or illness;
(2) suppress disease; For instance, align the pathology of experience or demonstration disease, symptom or illness or the individuality of symptom and carry out the inhibition (that is, stoping further developing of pathology and/or symptom) of disease, symptom or illness; With
(3) improve disease; For instance, align experience or show the pathology of disease, symptom or illness or the individuality of symptom carries out improve (that is, the reversing pathology and/or symptom) of disease, symptom or illness.
Chemical group, part or base
Term " C
1-C
6Acyl group " plan the C that expression is connected with the carbon of carbonyl
1-C
6Alkyl, wherein the definition of alkyl has and described identical definition herein; Some examples include, but is not limited to ethanoyl, propionyl, positive butyryl radicals, isobutyryl, valeryl, pentanoyl or the like.
Term " C
1-C
6Acyloxy " plan the acyl group that expression is connected with Sauerstoffatom, wherein acyl group has and described identical definition herein; Some embodiment are C for acyloxy
1-C
5Acyloxy, some embodiment are C for acyloxy
1-C
4Acyloxy.Some examples include, but is not limited to acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta acyloxy, hexylyloxy or the like.
Term " C
2-C
8Thiazolinyl " plan expression and have the group that contains 2 to 8 carbon of at least one carbon-carbon double bond; some embodiment are 2 to 7 carbon; some embodiment are 2 to 6 carbon; some embodiment are 2 to 5 carbon; some embodiment are 2 to 4 carbon; some embodiment are 2 to 3 carbon, and some embodiment have 2 carbon.E isomer and Z isomer contained in term " thiazolinyl ".In addition, term " thiazolinyl " comprises dialkylene and trialkenyl.Therefore, if there are two keys more than, so described key may be full E or full Z or its mixture.The example of thiazolinyl comprises vinyl, allyl group, crotyl, 3-butenyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexyl, 2,4-hexadienyl or the like.
Term " C
1-C
6Alkoxyl group " plan to represent and the direct-connected C as defined herein of Sauerstoffatom
1-C
6Alkyl, some embodiment are 1 to 5 carbon, and some embodiment are 1 to 4 carbon, and some embodiment are 1 to 3 carbon, and some embodiment are 1 or 2 carbon.Example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, isobutoxy, sec-butoxy or the like.
Term " C
1-C
8Alkyl " plan expression and contain the straight or branched carbon back of 1 to 8 carbon, some embodiment are 1 to 7 carbon, and some embodiment are 1 to 6 carbon; some embodiment are 1 to 5 carbon; some embodiment are 1 to 4 carbon, and some embodiment are 1 to 3 carbon, and some embodiment are 1 or 2 carbon.The example of alkyl include, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl, 1-methyl butyl [promptly-CH (CH
3) CH
2CH
2CH
3], the 2-methyl butyl [promptly-CH
2CH (CH
3) CH
2CH
3], n-hexyl, n-heptyl, n-octyl or the like.
Term " C
1-C
8The alkyl carboxamide groups " or " C
1-C
8The alkyl carboxylic acid amides " plan the single C that expression is connected with the carbon or the nitrogen of amide group
1-C
8Alkyl, wherein alkyl has and the identical definition of finding herein.C
1-C
8The alkyl carboxamide groups can be expressed from the next:
Example includes, but is not limited to N-methyl carboxylic acid amides, N-ethyl carboxylic acid amides, N-n-propyl carboxylic acid amides, N-sec.-propyl carboxylic acid amides, N-normal-butyl carboxylic acid amides, N-sec-butyl carboxylic acid amides, N-isobutyl-carboxylic acid amides, N-tertiary butyl carboxylic acid amides or the like.
Term " C
1-C
4Alkylidene group " plan expression and contain the C of 1 to 4 carbon
1-C
4Divalence straight chain carbon-based group, some embodiment are 1 to 3 carbon, and some embodiment are 1 to 2 carbon.In certain embodiments, alkylidene group is meant (for example)-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-and/or-CH
2CH
2CH
2CH
2-.
Term " C
2-C
4Alkenylene " plan expression and contain the C of 1 to 4 carbon and at least one two key
2-C
4Divalence straight chain carbon-based group, some embodiment are 2 to 3 carbon, and some embodiment are 2 carbon.In certain embodiments, alkenylene be meant (for example)-CH=CH-,-CH
2CH=CH-,-CH=CHCH
2-,-CH
2CH=CHCH
2-,-CH=CHCH
2CH
2-or the like.
Term " aryl-C
1-C
4Alkylidene group " plan the C of expression and aryl bond
1-C
4Alkylidene group, each group as defined herein.In certain embodiments, aryl-C
1-C
4Alkylidene group is meant (for example) benzyl (CH
2-phenyl), phenylethyl (CH
2CH
2-phenyl) or the like.
Term " heteroaryl-C
1-C
4Alkylidene group " plan the C of expression and heteroaryl bond
1-C
4Alkylidene group, each group as defined herein.In certain embodiments, heteroaryl-C
1-C
4Alkylidene group is meant (for example) pyridylmethyl (CH
2-pyridyl) or the like.
Term " C
1-C
8Alkyl sulphinyl " plan expression with have formula-S (O)-the C that is connected of the sulphur of sulfoxide group
1-C
8Alkyl, wherein alkyl has and described identical definition herein.Example includes, but is not limited to methylsulfinyl, ethyl sulfinyl, n-propyl sulfinyl, sec.-propyl sulfinyl, normal-butyl sulfinyl, sec-butyl sulfinyl, isobutyl-sulfinyl, tertiary butyl sulfinyl or the like.
Term " C
1-C
8Alkyl sulfonamide " plan the group shown in the expression hereinafter:
C wherein
1-C
8Alkyl has and described identical definition herein.
Term " C
1-C
8Alkyl sulphonyl " plan expression with have formula-S (O)
2-the C that connects of the sulphur of sulfuryl
1-C
8Alkyl, wherein alkyl has and described identical definition herein.Example includes, but is not limited to methyl sulphonyl, ethylsulfonyl, n-propyl alkylsulfonyl, sec.-propyl alkylsulfonyl, normal-butyl alkylsulfonyl, sec-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, tertiary butyl alkylsulfonyl or the like.
Term " C
1-C
8The alkyl sulfenyl " plan to represent and the sulphur atom (C that promptly-S-) is connected
1-C
8Alkyl, wherein alkyl has and described identical definition herein.It (is CH that example includes, but is not limited to the methyl sulfenyl
3S-), ethyl sulfenyl, n-propyl sulfenyl, sec.-propyl sulfenyl, normal-butyl sulfenyl, sec-butyl sulfenyl, isobutyl-sulfenyl, tertiary butyl sulfenyl or the like.
Term " C
1-C
8The alkyl urea groups " plan the group of expression-NC (O) N-, wherein a kind of situation is that two nitrogen are all through identical or different C
1-C
8Alkyl replaces, and wherein alkyl has and described identical definition herein.The example of alkyl urea groups includes, but is not limited to CH
3NHC (O) NH-, NH
2C (O) NCH
3-, (CH
3)
2NC (O) NH-, (CH
3)
2NC (O) NH-, (CH
3)
2NC (O) NCH
3-, CH
3CH
2NHC (O) NH-, CH
3CH
2NHC (O) NCH
3-or the like.
Term " C
2-C
8Alkynyl " plan to represent to contain 2 to 8 carbon and at least one carbon carbon triple-linked group, some embodiment are 2 to 4 carbon, some embodiment are 2 to 3 carbon, and some embodiment have 2 carbon.The example of alkynyl includes, but is not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base or the like.Term " alkynyl " comprises diine and three alkynes.
Group-NH planned to represent in term " amino "
2
Term " C
1-C
8Alkylamino " plan expression and the-basic alkyl that is connected of NH-, wherein alkyl has and described identical implication herein.Some examples include, but is not limited to methylamino, ethylamino, n-propyl amino, sec.-propyl amino, normal-butyl amino, sec-butyl amino, isobutylamino, tertiary butyl amino or the like.Some embodiment are " C
1-C
2Alkylamino ".
The aromatic series cyclic group of 6 to 10 carbon planned to represent to contain in term " aryl ".Example comprises phenyl and naphthyl.
Term " C
1-C
6Carbalkoxy " plan the C of expression carboxylic acid
1-C
6Alkyl ester, wherein alkyl as defined herein.Example includes, but is not limited to methoxycarbonyl [C (=O) OCH
3], ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, secondary butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, positive penta oxygen carbonyl, isoamyl oxygen carbonyl, uncle's penta oxygen carbonyl, new penta oxygen carbonyl, just own oxygen carbonyl or the like.
Group-CONH planned to represent in term " carboxylic acid amides "
2
Group-CO planned to represent in term " carboxyl "
2H; Be also referred to as hydroxy-acid group.
Group-CN planned to represent in term " cyano group ".
Term " C
3-C
7Cycloalkyl " plan expression and contain the saturated cyclic group of 3 to 7 carbon; Some embodiment contain 3 to 6 carbon; Some embodiment contain 3 to 5 carbon; Some embodiment contain 5 to 7 carbon; Some embodiment contain 3 to 4 carbon.Example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or the like.
Term " C
3-C
7Cycloalkylidene " plan expression and contain saturated rings two bases of 3 to 7 carbon; Some embodiment contain 3 to 6 carbon; Some embodiment contain 3 to 5 carbon; Some embodiment contain 5 to 7 carbon; Some embodiment contain 3 to 4 carbon.Example comprises cyclopropylidene, inferior cyclobutyl, cyclopentylidene, cyclohexylidene, inferior suberyl or the like.In certain embodiments, C
3-C
7Cycloalkylidene two bases may replace through 1,2 two; For example, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclopentyl, 1,2-cyclohexyl, 1,2-suberyl or the like.
Term " C
2-C
8Dialkyl amido " plan expression through two identical or different C
1-C
4The amino that alkyl replaces, wherein alkyl has and described identical definition herein.Some examples include, but is not limited to dimethylamino, methylethyl amino, diethylamino, methyl-propyl amino, isopropyl methyl amino, ethyl propyl amino, ethyl sec.-propyl amino, dipropyl amino, propyl group sec.-propyl amino or the like.Some embodiment are " C
2-C
4Dialkyl amido ".
Term " C
2-C
8The dialkyl group carboxamide groups " or " C
2-C
8The dialkyl group carboxylic acid amides " plan two identical or different alkyl that expression is connected with the vinegar amine groups, wherein alkyl has and described identical definition herein.C
2-C
8The dialkyl group carboxamide groups can be represented by following group:
C wherein
1-C
4Have and described identical definition herein.The example of dialkyl group carboxylic acid amides includes, but is not limited to N, N-dimethyl carboxylic acid amides, N-methyl-N-ethyl carboxylic acid amides, N, N-diethyl carboxylic acid amides, N-methyl-N-isopropyl propyl group carboxylic acid amides or the like.
Term " C
2-C
8The dialkyl group sulphonamide " plan in the following group shown in the expression hereinafter one:
C wherein
1-C
4Have and described identical definition herein, for example (but being not limited to) methyl, ethyl, n-propyl, sec.-propyl or the like.
Term " C
1-C
6Halogenated alkoxy " plan to represent and the direct-connected C as defined herein of Sauerstoffatom
1-C
6Haloalkyl.Example includes, but is not limited to difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, five fluorine oxyethyl groups or the like.
Term " C
1-C
6Haloalkyl " the defined herein C of plan expression
1-C
6Alkyl, wherein said alkyl replaces to replacing and replace full C entirely through a halogen
1-C
6Haloalkyl can be by formula C
nL
2n+1Expression, wherein L is that halogen and " n " they are 1,2,3,4,5 or 6; When having an above halogen, it may be identical or different and be selected from the group that is made up of F, Cl, Br and I, preferably F so, some embodiment are 1 to 5 carbon, some embodiment are 1 to 4 carbon, and some embodiment are 1 to 3 carbon, and some embodiment are 1 or 2 carbon.The example of haloalkyl includes, but is not limited to methyl fluoride, difluoromethyl, trifluoromethyl, chlorodifluoramethyl-, 2,2,2-trifluoroethyl, pentafluoroethyl group or the like.
Term " C
1-C
6The haloalkyl sulfinyl " plan expression with have formula-S (O)-the C that is connected of the sulphur atom of sulfoxide group
1-C
6Haloalkyl, wherein haloalkyl has and described identical definition herein.Example includes, but is not limited to trifluoromethyl sulphinyl base, 2,2,2-trifluoroethyl sulfinyl, 2,2-two fluoro ethyl sulfinyls or the like.
Term " C
1-C
6Halogenated alkyl sulfonyl " plan expression with have formula-S (O)
2-the C that connects of the sulphur atom of sulfuryl
1-C
6Haloalkyl, wherein haloalkyl has and described identical definition herein.Example includes, but is not limited to trifluoromethyl sulfonyl, 2,2,2-trifluoroethyl alkylsulfonyl, 2,2-difluoro ethylsulfonyl or the like.
Term " C
1-C
6The haloalkyl sulfenyl " the direct C that is connected with sulphur of plan expression
1-C
6Haloalkyl, wherein haloalkyl has and described identical implication herein.It (is CF that example includes, but is not limited to the trifluoromethyl sulfenyl
3S-is also referred to as the trifluoromethyl sulfenyl), 1,1-two fluoro ethyl sulfenyls, 2,2,2-trifluoroethyl sulfenyl or the like.
Term " halogen " or " halogen " plan to represent fluorine, chlorine, bromine or iodine base.
It is the aromatic ring system of monocycle, two condensed ring or three condensed ring that term " heteroaryl " plans to express possibility, and wherein the heteroatoms of the group of at least one ring carbon through being selected from (but being not limited to) and being made up of O, S and N is replaced, and wherein said N can be randomly through H, C
1-C
4Acyl group or C
1-C
4Alkyl replaces.In certain embodiments, heteroaryl is 6 yuan of heteroaryls (for example, pyridyl, pyrazinyls or the like).In certain embodiments, heteroaryl is 5 yuan of heteroaryls (for example, pyrryl, thiazolyl, triazolyl, 1,3,4-thiadiazolyl group, 1,2,3-thiadiazolyl groups or the like).The example of heteroaryl includes, but is not limited to pyridyl, benzofuryl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl, quinolyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl-, isoquinolyl, quinazolyl, quinoxalinyl or the like.In certain embodiments, heteroatoms is selected from the group that (but being not limited to) is made up of O, S and N, and wherein N replaces (being NH) through H, and example includes, but is not limited to pyrryl, indyl, 1H-benzimidazolyl-2 radicals-Ji or the like.
Two bases of heteroaryl ring planned to represent in term " inferior heteroaryl ", and wherein heteroaryl as defined herein.In certain embodiments, inferior heteroaryl is meant 6 yuan of inferior heteroaryls, for example, and pyridazine, pyridine and pyrimidine as follows respectively:
In certain embodiments, inferior heteroaryl is meant 5 yuan of inferior heteroaryls, for example, [1,2,4] thiadiazoles, 4H-[1 as follows respectively, 2,4] triazole and [1,3,4] thiadiazoles:
Term " C
3-C
7Inferior heterocyclic radical " plan to represent heterocyclic two bases that wherein heterocycle is as defined herein.In certain embodiments, inferior heterocyclic radical is meant (for example) tetrahydropyrans, tetrahydrofuran (THF), piperidines, tetramethyleneimine or the like; These groups can be distinguished as follows the expression:
Term " C
3-C
7Heterocycle " or " C
3-C
7Heterocyclic radical " plan expression non-aromatic carbocyclic ring (i.e. C as defined herein
3-C
7Cycloalkyl or C
4-C
7Cycloalkenyl group), wherein one or two ring carbon through be selected from (but being not limited to) by O, S, S (=O), S (=O)
2, the group that forms of NH the heteroatoms displacement, wherein said N can be randomly through C as described herein
1-C
4Alkyl replaces, and in certain embodiments, nitrogen is randomly through C
1-C
4Acyl group or C
1-C
4Alkyl replaces, and therefore ring carbon atom forms carbonyl or thiocarbonyl group randomly through oxo base or thio group replacement.Heterocyclic group can be connected/bond with any available annular atoms (for example encircling carbon, ring nitrogen or the like).Heterocyclic group is 3 yuan, 4 yuan, 5 yuan, 6 yuan or 7 yuan of rings.The example of heterocyclic group includes, but is not limited to aziridine-1-base, aziridine-2-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, piperidines-1-base, piperidines-2-base, piperidines-3-base, piperidin-4-yl, morpholine-2-Ji, morpholine-3-base, morpholine-4-base, piperazine-1-base, piperazine-2-base, piperazine-3-base, piperazine-4-base, tetramethyleneimine-1-base, tetramethyleneimine-2-base, tetramethyleneimine-3-base, [1,3]-dioxolane-2-base, thiomorpholine-4-base, [1,4] Evil azepan-4-bases, 1,1-dioxo-1 λ
6-thiomorpholine-4-base, azepan-1-base, azepan-2-base, azepan-3-base, azepan-4-base, tetrahydrochysene-furans-2-base, tetrahydrochysene-furans-3-base, tetrahydrochysene-pyrans-2-base, tetrahydrochysene-pyrans-3-base, tetrahydrochysene-pyrans-4-base or the like.
Group-OH planned to represent in term " hydroxyl ".
Group-NO planned to represent in term " nitro "
2
Substituting group=O planned to represent in term " oxo base ", and correspondingly, therefore when carbon warp " oxo base " replaced, the new group that is produced together by carbon and oxo base was a carbonyl.
Group C planned to represent in term " phenyl "
6H
5-.
Two bases of benzene planned to represent in term " phenylene ".In certain embodiments, phenylene plans to represent 1, the 2-phenylene, and in certain embodiments, phenylene plans to represent 1, the 3-phenylene, in certain embodiments, and phenylene plan expression 1, the 4-phenylene, it can followingly be represented:
Group-SO planned to represent in term " sulphonamide "
2NH
2
Group-SH planned to represent in term " mercaptan ".
The compounds of this invention:
An aspect of of the present present invention relates to some suc as formula the compound shown in (Ia):
Or its pharmaceutically acceptable salt, hydrate or solvate;
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, W and ring A have with this paper above and hereinafter described identical definition.
In certain embodiments, the present invention relates to compound as described herein, condition is ring B and R
1-W-S (O)
2The sulphur of-group not with the ring A the adjacent ring Atom Bonding.
In certain embodiments, the present invention relates to compound as described herein, condition is if ring A is 1,3-phenylene or 1, and the 4-phenylene, and W is C
3-C
7Inferior heterocyclic radical is so with R
1-W-S (O)
2The annular atoms of the W of the direct bond of sulphur of-group is not a nitrogen.
In certain embodiments, the present invention relates to compound as described herein, condition is if W is C
3-C
7Inferior heterocyclic radical is so with-S (O)
2-the annular atoms of W of the direct bond of sulphur be not nitrogen.
In certain embodiments, the present invention relates to compound as described herein except that following compound:
It has chemical name: 4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-3-methane sulfonyl-biphenyl-4-formic acid.
In certain embodiments, the present invention relates to compound as described herein except that following compound:
It has chemical name: 3-ethane alkylsulfonyl-4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-biphenyl-4-formic acid.
In certain embodiments, the present invention relates to compound as described herein except that following compound:
It has chemical name: 4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-3-(propane-2-alkylsulfonyl)-biphenyl-4-formic acid.
In certain embodiments, the present invention relates to separated formula as described herein (Ia) compound.
In certain embodiments, the present invention relates at the external separated formula as described herein of individuality (Ia) compound.
In certain embodiments, separated formula (Ia) compound has greater than about 0.1%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about purity of 95%, about 98% or about 99%.
Should be appreciated that, be described in also capable of being combined being provided among the single embodiment of some feature of the present invention in the content of indivedual embodiment for the clarity purpose.On the contrary, the of the present invention various features that are described in the content of single embodiment for the terseness purpose also can provide separately or with any suitable sub-portfolio form.About by contained variable (for example, R in the described general chemical formula [for example (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (Io), (Iq), (Is) etc.] herein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, W, ring A etc.) all combinations of embodiment of represented chemical group are covered by among the present invention clearly, as it clearly through disclose, its degree contains compound as stable compound (that is, can through the active compound of separation, sign and test organisms) for these combinations.In addition, all sub-portfolios of the chemical group of listing in the embodiment that describes these variablees and all sub-portfolios of described herein purposes and medical indications also are covered by among the present invention clearly, disclose the same separately clearly in herein as this sub-portfolio of chemical group and the sub-portfolio of purposes and medical indications.
As used herein, at least one hydrogen atom of " being substituted " expression chemical group is through non-hydrogen substituting group or group displacement, and described non-hydrogen substituting group or group may be unit price or divalence.When substituting group or group are divalence, should be appreciated that so this group further replaces through another substituting group or group.When the chemical group when herein " was substituted ", it can have up to all replacements of valence state; For instance, methyl can replace through 1,2 or 3 substituting group, and methylene radical can replace through 1 or 2 substituting group, and phenyl can replace through 1,2,3,4 or 5 substituting group, and naphthyl can replace or the like through 1,2,3,4,5,6 or 7 substituting group.Similarly, " replace " the substituting group replacement of the whole numbers that are meant that group is allowed to described group physically through a substituting group through one or more substituting groups.In addition, when group when an above group replaces, its can be identical or its can be different.
The compounds of this invention also can comprise tautomeric form, for example keto-enol tautomerism body or the like.Tautomeric form can be in equilibrium state or be locked as a kind of form on the space by suitably being substituted in.Should be appreciated that various complementary isomeric form are all in the scope of The compounds of this invention.As an illustration, when W is 3,5-two replaces-1,2, during the 4-triazolyl, can there be three kinds of possible tautomers so, although and may only show a kind of formula, and should be appreciated that described formula contains all possible tautomer, described possible tautomer is showed in down:
Should be appreciated that tautomeric form also can have corresponding name for each tautomer.Therefore, the present invention includes the various name titles of all tautomers and all tautomers.
The compounds of this invention also can comprise all isotropic substances of the atom that exists in intermediate and/or the final compound.Isotropic substance comprises having the same atoms number but those atoms of different mass number.For instance, the isotropic substance of hydrogen comprises deuterium and tritium.
Should be appreciated that and understand that The compounds of this invention may have one or more chiral centres, and therefore can enantiomer and/or diastereomeric form exist.Should be appreciated that the present invention expands to and contains all these enantiomers, diastereomer and its mixture, includes, but is not limited to racemoid.Therefore, some embodiments of the present invention relate to the The compounds of this invention as the R enantiomer.In addition, some embodiments of the present invention relate to the The compounds of this invention as the S enantiomer.In the example that has an above chiral centre, some embodiments of the present invention comprise the compound as RS or SR enantiomer so.In other embodiments, The compounds of this invention is RR or SS enantiomer.Should be appreciated that unless otherwise indicated or show, otherwise The compounds of this invention is planned all possible indivedual enantiomers of expression and its mixture, as each personal structure that is provided is individually named.
An aspect of of the present present invention relates to some suc as formula the compound shown in (Ia):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
1Be selected from the group that forms by following each group: H, C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6Haloalkyl sulfenyl, C
3-C
7Heterocyclic radical, hydroxyl, mercaptan, nitro, phenyl and sulphonamide, and each group randomly replaces through 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through 1,2,3 or 4 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro, oxo base and sulphonamide are formed;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene, C
3-C
7Inferior heterocyclic radical or phenylene, each group randomly replaces through 1,2,3,4,5,6,7 or 8 substituting group, and described substituting group independently is selected from by C
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen, hydroxyl and oxo base are formed;
Ring A is the R that respectively hangs oneself
12, R
13, R
14And R
151 of replacement, 3-phenylene or 1,4-phenylene, wherein R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed; Or
Ring A is separately randomly through R
16, R
17And R
186 yuan of inferior heteroaryls or 5 yuan of inferior heteroaryls, wherein R of replacing
16, R
17And R
18Independently be selected from separately by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
2, R
3, R
4And R
5Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
6, R
7, R
8And R
9Independently be selected from by H, C separately
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen and hydroxyl are formed;
And
R
10And R
11Independently be selected from by H, C separately
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
7Cycloalkyl, aryl, heterocyclic radical, heteroaryl, aryl-C
1-C
4Alkylidene group and heteroaryl-C
1-C
4The group that alkylidene group is formed, and each R
10And R
11Randomly replace through 1,2,3,4 or 5 substituting group, described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
Or
R
10And R
11The nitrogen-atoms of both institute's bonds forms the C that randomly replaces through 1,2,3,4,5 or 6 substituting group together with it
3-C
7Heterocyclic radical, described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro, oxo base and sulphonamide are formed, and C
1-C
8Alkyl is randomly through C
1-C
6Alkoxyl group or hydroxyl replace;
Condition is:
1) ring B and R
1-W-S (O)
2The sulphur of-group not with the ring A the adjacent ring Atom Bonding;
2) if ring A is 1,3-phenylene or 1, the 4-phenylene, and W is C
3-C
7Inferior heterocyclic radical is so with R
1-W-S (O)
2The annular atoms of the W of the direct bond of sulphur of-group is not a nitrogen;
And
3) described compound is not:
4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-3-methane sulfonyl-biphenyl-4-formic acid;
3-ethane alkylsulfonyl-4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-biphenyl-4-formic acid; Or
4 '-[2-(2-hydroxyl-2-phenyl-ethylamino)-ethyl]-3-(propane-2-alkylsulfonyl)-biphenyl-4-formic acid.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Ic):
Each variable in its Chinese style (Ic) have with this paper above and hereinafter described identical implication.
In certain embodiments, the present invention relates to compound as described herein, condition is if R
12, R
13, R
14All be H, R so
15It or not carboxyl.
Some embodiments of the present invention relate to some compound, and wherein encircling A is 1, the 3-phenylene.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Ie):
Each variable in its Chinese style (Ie) have with this paper above and hereinafter described identical implication.
In certain embodiments, the present invention relates to compound as described herein, condition is if R
1-W-S (O)
2-group and ring B are at annular atoms 1 and annular atoms 3 places and ring A bond (for example suc as formula shown in (Ie)), and R
12, R
13, R
14And R
15Three groups all are hydrogen, R so in the group
12, R
13, R
14And R
15The 4th group in the group is not carboxyl.Should be appreciated that the numerical value title of annular atoms 1 and annular atoms 3 is 1 of finger ring A, 3-substitute mode and may maybe may not correspond to actual numerical value title in the chemical name.
In certain embodiments, the present invention relates to compound as described herein, condition is R
15It or not carboxyl.
Some embodiments of the present invention relate to some compound, and wherein encircling A is 1, the 4-phenylene.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Ig):
Each variable in its Chinese style (Ig) have with this paper above and hereinafter described identical implication.
In certain embodiments, R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
8The group that alkyl, carboxyl and halogen are formed.
In certain embodiments, R
12, R
13, R
14And R
15Independently be selected from separately by H ,-CH
3, the group that forms of carboxyl, Cl and Br.
In certain embodiments, R
12, R
13, R
14And R
15H respectively does for oneself.
Some embodiments of the present invention relate to some compound, and wherein encircling A is 6 yuan of inferior heteroaryls.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Ii):
Wherein, X is N or CH; Y is N or CH; And Z is N or CH; Condition is that at least one X, Y and Z are N; And each surplus variable in the formula (Ii) have with this paper above and hereinafter described identical implication.
Some embodiments of the present invention relate to some compound, and wherein encircling A is 5 yuan of inferior heteroaryls.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Ik):
Wherein, J is N or NH; And
E and G independently are selected from N or S separately, and condition is that at least one E and G are N; And each surplus variable in the formula (Ik) have with this paper above and hereinafter described identical implication.
In certain embodiments, R
1Be selected from by H, C
1-C
6Alkoxyl group, amino, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, C
3-C
7The group that heterocyclic radical, hydroxyl and phenyl are formed, and separately randomly through cyano group or C
3-C
7Cycloalkyl substituted; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and C
5-C
7Heterocycle randomly replaces through the oxo base.
In certain embodiments, R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and C
5-C
7Heterocycle randomly replaces through the oxo base.
In certain embodiments, R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed.
In certain embodiments, R
1Be H or C
1-C
6Alkoxyl group.
In certain embodiments, R
1Be H.
In certain embodiments, R
1Be C
1-C
6Alkoxyl group.
In certain embodiments, R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl.
In certain embodiments, W is C
1-C
4Alkylidene group, C
1-C
4Alkenylene, C
3-C
7Cycloalkylidene or phenylene, each group is randomly through C
1-C
3Alkyl replaces.
In certain embodiments, W is C
1-C
4Alkylidene group or C
2-C
4Alkenylene, each group is randomly through C
1-C
3Alkyl replaces.
In certain embodiments, W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed.Should be appreciated that 4-tetrahydropyrans-2-base and 3-tetrahydropyrans-5-base are meant following formula:
In certain embodiments, W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-and 1, the group that the 3-cyclopentylidene is formed.
In certain embodiments, R
1Form the group that is selected from following group or its any sub-portfolio together with W:
In certain embodiments, W is selected from by-CH
2CH
2-and-group that HC=CH-forms.
In certain embodiments, W is-CH
2CH
2-.
In certain embodiments, W is-HC=CH-.
In certain embodiments, the present invention relates to compound as described herein, condition is R
1Form together with W and to remove-CH
3Outside group (be R
1With W one time-out be not methyl).
In certain embodiments, the present invention relates to compound as described herein, condition is R
1Form together with W and to remove-CH
2CH
3Outside group (be R
1With W one time-out be not ethyl).
In certain embodiments, the present invention relates to compound as described herein, condition is R
1Form together with W and to remove-CH (CH
3)
2Outside group (be R
1With W one time-out be not sec.-propyl).
In certain embodiments, R
2, R
3, R
4And R
5Each is H naturally.
In certain embodiments, R
6, R
7, R
8And R
9Each is H naturally.
In certain embodiments, the present invention relates to compound as described herein, condition is if a R
10And R
11Group is aryl-C
1-C
4Alkylidene group, so described aryl-C
1-C
4The alkylidene group randomly substituting group outside 1,2,3,4 or 5 hydroxyl-removal replaces.
In certain embodiments, the present invention relates to following compound, wherein R
10And R
11Independently be selected from by H, C separately
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
7Cycloalkyl, aryl, heterocyclic radical, heteroaryl, aryl-C
1-C
4Alkylidene group and heteroaryl-C
1-C
4The group that alkylidene group is formed, and each R
10And R
11Randomly replace through 1,2,3,4 or 5 substituting group, described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, mercaptan, nitro and sulphonamide are formed.
In certain embodiments, R
10And R
11Independently be selected from by H, C separately
1-C
8Alkyl, aryl-C
1-C
4Alkylidene group and heteroaryl-C
1-C
4The group that alkylidene group is formed;
Or
R
10And R
11The nitrogen-atoms of both institute's bonds forms the C that randomly replaces through 1 or 2 substituting group together with it
3-C
7Heterocyclic radical, described substituting group independently is selected from by C
1-C
8The group that alkyl, halogen and hydroxyl are formed, and C
1-C
8Alkyl is randomly through C
1-C
6Alkoxyl group or hydroxyl replace.
In certain embodiments, R
10And R
11Independently be selected from by H, C separately
1-C
8Alkyl, aryl-C
1-C
4Alkylidene group and heteroaryl-C
1-C
4The group that alkylidene group is formed.
In certain embodiments, R
10And R
11The nitrogen-atoms of both institute's bonds forms the C that randomly replaces through 1 or 2 substituting group together with it
3-C
7Heterocyclic radical, described substituting group independently is selected from by C
1-C
8The group that alkyl and halogen are formed.
In certain embodiments, R
10And R
11Independently be selected from separately by H ,-CH
3,-CH
2CH
3,-CH (CH
3)
2With-CH
2The group that-phenyl is formed.
In certain embodiments, R
10And R
11Both nitrogen-atoms of institute's bond form C together with it
3-C
7Heterocyclic radical, it is selected from by tetramethyleneimine-1-base, 2-methyl-tetramethyleneimine-1-base, 2,5-dimethyl-tetramethyleneimine-1-base, 3-hydroxyl-tetramethyleneimine-1-base, 3, the group that 3-two fluoro-tetramethyleneimine-1-base, 3-hydroxymethyl-tetramethyleneimine-1-base, piperidines-1-base, morpholine-4-base, thiomorpholine-4-base, piperazine-1-base and 4-methyl-piperazine-the 1-base is formed.
In certain embodiments, R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
In certain embodiments, R
10And R
11The nitrogen-atoms of both institute's bonds forms (R)-2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Im):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
8The group that alkyl, carboxyl and halogen are formed;
R
1Be selected from by H, C
1-C
6Alkoxyl group, amino, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, C
3-C
7The group that heterocyclic radical, hydroxyl and phenyl are formed, and each group is randomly through cyano group or C
3-C
7Cycloalkyl substituted; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and C
5-C
7Heterocycle randomly replaces through the oxo base;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene or phenylene, each group is randomly through C
1-C
3Alkyl replaces; And
R
10And R
11Independently be selected from by H, C separately
1-C
8Alkyl, aryl-C
1-C
4Alkylidene group and heteroaryl-C
1-C
4The group that alkylidene group is formed;
Or
R
10And R
11The nitrogen-atoms of both institute's bonds forms the C that randomly replaces through 1 or 2 substituting group together with it
3-C
7Heterocyclic radical, described substituting group independently is selected from by C
1-C
8The group that alkyl, halogen and hydroxyl are formed, and C
1-C
8Alkyl is randomly through C
1-C
6Alkoxyl group or hydroxyl replace.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Im):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
8The group that alkyl, carboxyl and halogen are formed;
R
1Be selected from by H, C
1-C
6Alkoxyl group, amino, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, C
3-C
7The group that heterocyclic radical, hydroxyl and phenyl are formed, and each group is randomly through cyano group or C
3-C
7Cycloalkyl substituted; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene or phenylene, each group is randomly through C
1-C
3Alkyl replaces; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Im):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Independently be selected from separately by H ,-CH
3, the group that forms of carboxyl, Cl and Br;
R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and C
5-C
7Heterocycle randomly replaces through the oxo base;
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed; And
R
10And R
11Both nitrogen-atoms of institute's bond form C together with it
3-C
7Heterocyclic radical, it is selected from by tetramethyleneimine-1-base, 2-methyl-tetramethyleneimine-1-base, 2,5-dimethyl-tetramethyleneimine-1-base, 3-hydroxyl-tetramethyleneimine-1-base, 3, the group that 3-two fluoro-tetramethyleneimine-1-base, 3-hydroxymethyl-tetramethyleneimine-1-base, piperidines-1-base, morpholine-4-base, thiomorpholine-4-base, piperazine-1-base and 4-methyl-piperazine-the 1-base is formed.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Im):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Independently be selected from separately by H ,-CH
3, the group that forms of carboxyl, Cl and Br;
R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base;
W is selected from the group that is made up of following each group :-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the 4-phenylene; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Im):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Io):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Iq):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Is):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
Ring A is selected from:
X is N or CH; Y is N or CH; And Z is N or CH; Condition is that at least one X, Y and Z are N;
J is N or NH; And E and G independently are selected from N or S separately, and condition is that at least one E and G are N;
R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with W-SO
2Group and W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A;
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed; And
R
10And R
11Both nitrogen-atoms of institute's bond form C together with it
3-C
7Heterocyclic radical, it is selected from by tetramethyleneimine-1-base, 2-methyl-tetramethyleneimine-1-base, 2,5-dimethyl-tetramethyleneimine-1-base, 3-hydroxyl-tetramethyleneimine-1-base, 3, the group that 3-two fluoro-tetramethyleneimine-1-base, 3-hydroxymethyl-tetramethyleneimine-1-base, piperidines-1-base, morpholine-4-base, thiomorpholine-4-base, piperazine-1-base and 4-methyl-piperazine-the 1-base is formed.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Is):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
Ring A is selected from:
X is N or CH; Y is N or CH; And Z is N or CH; Condition is that at least one X, Y and Z are N;
J is N or NH; And E and G independently are selected from N or S separately, and condition is that at least one E and G are N;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
Some embodiments of the present invention relate to some suc as formula the compound shown in (Is):
Or its pharmaceutically acceptable salt, hydrate or solvate;
Wherein:
Ring A is selected from by 1,4-phenylene, 1,3-phenylene, 4-carboxyl-1,3-phenylene, 4-methyl isophthalic acid, 3-phenylene, pyridine-2,5-subunit, pyrimidine-2,5-subunit and 1,2,4-thiadiazoles-3, the group that the 5-subunit is formed;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, group that hydroxyl, phenyl, morpholine-4-base, tetrahydrochysene-pyrans-4-base, carboxyl, 4-cyano group piperidines-1-base, amino, cyclohexyl amino, methylamino, tetrahydrochysene-pyrans-2-base is formed; Or
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-HC=CH-, 1, the 3-cyclopentylidene ,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base ,-CH
2HC=CH-,-CH
2CH
2C (=O)-,-CH
2CH (CH
3) CH
2-,-CH
2CH (CH
3)-and piperidines-2, the group that the 4-subunit is formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
In certain embodiments, R
1Form the group that is selected from following group or its any sub-portfolio together with W:
Some embodiments of the present invention comprise each combination of the compound that one or more are selected from the following group shown in the Table A.
Table A
Some embodiments of the present invention comprise that one or more are selected from each combination of the compound of the following group shown in the table B.
Table B
In addition, individual compound of the present invention and chemical species (for example those compounds of visible in the Table A comprise its diastereomer and enantiomer) are contained its all pharmaceutically acceptable salt, solvate and hydrate especially.
Some embodiments of the present invention relate to the method and the intermediate of formula (Ia) compound that is applicable to that preparation is novel.The general method that is used for preparing The compounds of this invention is showed in Fig. 1 and comes across in the operational instances hereinafter to the exemplary reagent and the program of Fig. 7 and these reactions.Can protect and go to protect (for example referring to Green by general known program in the affiliated technical field, T.W. (Greene, T.W.) and military thatch, P.G.M. (Wuts, P.G.M.), protecting group in the organic synthesis (Protecting Groups in Organic Synthesis), the 3rd edition, 1999 [prestige is found (Wiley)]; Be incorporated herein in full by reference).
Should be appreciated that each diastereomer, each enantiomer and its mixture of each compound disclosed herein and general formula contained in the present invention, the specific stereochemistry title of each personal each chiral carbon individually discloses as it.By (for example using separation that the well-known the whole bag of tricks of person skilled in the art realizes individual isomers, recrystallize of chirality HPLC, diastereo-isomerism mixture or the like) or the selectivity of individual isomers synthetic (for example, enantiomerism selectivity synthetic or the like).Show representative example herein.
Indication that prevents and/or treats and method
Histamine [2-(imidazol-4 yl) ethamine] is brought into play its physiological role by four kinds of different G protein-coupled receptors (GPCR) (being called H1, H2, H3 and H4).Histamine H 3 receptor was identified first in nineteen eighty-three, measure at that time the H3 acceptor as the synthetic and autoreceptor that discharges of control histamine (referring to Ah allowing (Arrang) people of etc.ing, natural (Nature), nineteen eighty-three, 302,832-7).Verified at least four kinds of human splicing variants and three kinds of rat splicing variants have functionally active (Pa Sani people such as (Passani) in the pharmacology analysis, pharmacology science trend (Trends in Pharmacol.Sci.), 2004,25,618-625).Rat and human histamine H 3 receptor be the presentation group activity that becomes second nature also, even this represents its also transducible signal under the situation that does not have part.Histamine H 3 receptor also serves as heteroreceptor (heteroceptor), its adjusting comprises that the release of multiple other transmitter substance of thrombotonin, vagusstoff, Dopamine HCL (dopamine) and norepinephrine is (referring to Blang people such as (Brown), neurobiology progress (Prog.Neurobiol.), calendar year 2001,63,637-672).Therefore, exist the multiple treatment of the part of target histamine H 3 receptor is used, wherein part serves as antagonist or inverse agonist (about comment referring to Li Yousi people such as (Leurs), naturally comment: drug discovery (Nat.Rev.Drug.Discov.), 2005,4,107-120; Pa Sani people such as (Passani), pharmacology science trend (TrendsPharmacol.Sci.), 2004,25,618-625).
Therefore, preclinical study identified multiple can be by the indication of histamine H 3 receptor antagonists and inverse agonist (for example The compounds of this invention) treatment.It is believed that compound disclosed herein is applicable to treats and/or prevents some kinds of diseases and illness, and is applicable to and improves its symptom.These compounds can use or make up other compound separately and use to treat and/or prevent disease and illness.Without stint, these diseases and illness comprise following disease and illness.
Showed histamine H 3 receptor antagonists increase awakening (woods J.S. (Lin J.S.) people of etc.ing for example, brain is studied (BrainResearch), nineteen ninety, 523,325-330).This effect shows that the H3 receptor antagonist can be used for sleep and Arousal disorders (Pa Mendier people such as (Parmentier), Journal of Neuroscience (J.Neurosci.),, 22,7695-7711 in 2002; Li Niu people such as (Ligneau), pharmacology and experimental therapeutic magazine (J.Pharmacol.Exp.Ther.), 1998,287,658-666).For instance, histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of with the different pathological symptom (for example, sleep apnea and Parkinson's disease (Parkinson ' s disease)) relevant somnolence syndromes or the situation relevant with mode of life, for example the somnolence on daytime that causes owing to the sleep deprivation of working at night, excessively working or the time difference causing is (referring to Pa Sani people such as (Passani), pharmacology science trend (Trends Pharmacol.Sci.), 2004,25,618-625).Somnolence is a kind of main public health problem, because its risk that has high incidence (19%-37% of total population) and cause work and traffic accident.
Sleep apnea (perhaps sleep apnea) is a kind of common somnopathy of breathing briefly interrupted between sleep period that is characterized as.Being called as apneic these incidents continues repeatedly to take place more than 10 seconds or 10 seconds and at whole night.The people who suffers from sleep apnea partly awakens when it does one's utmost to breathe, but they may not can be appreciated that it is sleep disordered morning.The common type of sleep apnea is obstructive sleep apnea (OSA), and it is that soft tissue by the throat rear portion loosens the blocking-up air passageways and causes.Centric sleep apnea (CSA) is to be caused by the irregularities of brain to the normal signal of breathing.The significant symptom of described illness is that excessive daytime is drowsiness.Other symptom of sleep apnea comprises insomnia, snore thunderously (one period quietness, then asthma), sleeping, morning headache, attention are concentrated difficult, irritated, forgetful, mood or behavior change, weight increase, heart rate quickening, anxiety and dysthymia disorders by day.
Although it is carry out research and the test of two more than ten years, known seldom based on the treatment for obstructive sleep apnea of medicine.Oral methyl xanthine theophylline (chemically similar with caffeine (caffeine)) can reduce the occurrence number of apnea, but also may produce such as side effects such as palpitaition and insomnias.Theophylline is generally invalid in suffering from the grownup of OSA, but is used for the treatment of CSA sometimes, and suffers from apneic baby and children.In 2003 and 2004, reported the incidence that some neuroactive drugs (especially modern thymoleptic comprise mirtazapine (mirtazapine)) reduce obstructive sleep apnea.When other treatment is not exclusively treated OSA, sometimes open the drowsiness or somnolence on daytime that medicine is treated the patient.The scope of these medicines be from such as Amphetamine stimulants such as (amphetamine) to modern anti-narcolepsy medicine.Till 2004, visible medicine modafinil (modafinil) with the use of this effect in continuous increase.
In addition, for example, histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of narcolepsy (Tai Fude people such as (Tedford), Society for Neuroscience's digest (Soc.Neurosci.Abstr.),, 25,460.3 in 1999).Narcolepsy is the most common excessive daytime drowsiness (EDS), hypnolepsy and the rapid eye movement (REM of being characterized as; Rapid eyemovement) the neuroscience symptom of somnopathy.The principal character of narcolepsy is overpowering excessive daytime drowsiness (EDS), even also be like this behind enough nighttime sleeps.The people who suffers from narcolepsy can might become drowsy or sleeping at unsuitable when and where usually.In addition, nighttime sleep may be mingled with frequently and waking up.The classical symptom of narcolepsy comprises that (for example) damping off, and it is breaking out of muscle function forfeiture, and scope is collapsed to complete health from slight weakness (for example neck or knee are tired, facial muscles lax or slurred speech).Its outbreak may be by such as laugh, sudden emotional reactions such as angry, stunned or fear cause, and may continue the several seconds and arrive several minutes.Another symptom of narcolepsy is a sleep paralysis, and it is meant temporarily can't talk when waking up or move.Other symptom comprises (for example): hypnagogic hallucination, and it is meant experiences as lifelike, the common frightening dreamland that occurs when sleepy, sleeping and/or clear-headed; And automatism, it is meant that someone continues to carry out some activity (talk, get things together etc.) but forget when waking up to carry out these activities during narcolepsy.Drowsiness, sleep paralysis and hypnagogic hallucination on daytime also can appear in the people's people of sleep insuffience (for example suffer from extremely) who does not have a narcolepsy.It has been generally acknowledged that and have only narcolepsy just can occur dampinging off.
Symptom is only treated in the treatment that is used for narcolepsy at present, and does not treat the potential cause of disease.For dampinging off and REM sleep symptom, prescription drug is the medicine of antidepressant drug and other inhibition REM sleep.Usually use such as Methylphenidylacetate (methylphenidate) (Ritalin (Ritalin)), Amphetamine (amphetamine (Adderall)), dexamphetamine (dextroamphetamine) (Dextroamphetamine (Dexedrine)), meth (methamphetamine) (methyl amphetamine (Desoxyn)), modafinil stimulants such as (protecting clear-headed (Provigil)) and treat drowsiness.The other medicines that use are morphine monomethyl ether (codeine) and Selegiline (selegiline).Use clomipramine (clomipramine), imipramine (imipramine) or protriptyline (protriptyline) to treat and damping off, just need this treatment in severe case but have only.Dampinging off that food and drug administration (Food and DrugAdministration) approval use medicine gamma hydroxybutyrate (GHB) (Ai Ruimu (Xyrem)) treatment is relevant with narcolepsy is drowsiness with excessive daytime.
What is interesting is, showed recently modafinil (protect clear-headed) increase the hypothalamus histamine release (stoneman people such as (Ishizuka), neuroscience communication (Neurosci.Lett.), 2003,339,143-146).
In addition, use the many Bermans of typical narcolepsy (Doberman) model that the recent research of non-imidazoles histamine H 3 receptor antagonists is showed that histamine H 3 receptor antagonists can reduce the number of times and the outbreak time length (Ka Lutesi (Carruthers) of the outbreak of dampinging off, Europe histamine EASD's annual meeting (Ann.Meet.Eur.Histamine Res.Soc.), 2004, digest, the 31st page).
In a word, histamine H 3 receptor antagonists can be used for the treatment of with inverse agonist and/or prevention and the drowsiness pathologies associated of excessive daytime (for example hypersomnia, narcolepsy, sleep apnea, time zone change obstacle) and with drowsiness other relevant illness of excessive daytime (for example fibromyalgia and multiple sclerosis) (Pa Mendier people such as (Parmentier), Journal of Neuroscience (J.Neurosci.), 2002,22,7695-7711; Li Niu people such as (Ligneau), pharmacology and experimental therapeutic magazine (J.Pharmacol.Exp.Ther.), 1998,287,658-666).Other symptom comprises because of the hyper somnolence that work in shifts causes, medical venereal disease disease, mental illness, narcolepsy, primary hypersomnia or the like.Also can be weak and feeble after workman, sleep deprivation, anesthesia in shifts, as using histamine H 3 receptor antagonists and inverse agonist to promote awakening or vigilance once in a while in the drowsiness of pharmacological agent side effect, military use or the like.
In addition, awakening is to comprise the prerequisite of some kinds of brain functions of attention, study power and memory and essential by the appropriate action of responding environment challenge.Showed that histamine H 3 receptor antagonists and inverse agonist improve cognitive performance (Chinese cock (Hancock) and Fox (Fox) in various animal models, the milestone of pharmacotherapy (Milestonesin Drug Therapy), cloth Kaffirs section (Buccafusco) compiles, 2003).These compounds can and can increase alertness as cognitive promotor.Therefore, histamine H 3 receptor antagonists and inverse agonist can be used for the impaired aging or degeneration illness of alertness, attention and memory, for example are used for alzheimer's disease or other dementia.
Alzheimer's disease (AD) (a kind of nervus retrogression illness) be dementia most commonly encountered diseases because of.Its Clinical symptoms is the decline of carrying out property cognitive function and neural mental symptom and behavior change.The most significant early symptom is the loss of memory, and it is usually expressed as slightly forgetful, constantly becomes more remarkable along with progression of disease is forgetful, and it keeps relatively recalls than the reporter.Along with illness progress, function (for example make decision and the work out a scheme) field that cognitive (intelligence) infringement extends to language, technique action, identification and is closely related with the frontal lobe and the temporal lobe of brain.Still the cure method of not having at present AD, but have the medicine that the symptom benefit is provided, particularly about short-term memory infringement aspect.These medicines comprise: acetylcholinesterase depressant, for example bright (rivastigmine) (Exelon (Exelon)) of E2020 (donepezil) (aricept (Aricept)), lycoremine (galantamine) (Lei Zhading (Razadyne)) and Li Fansi; And nmda antagonist, for example memantine (memantine).
Histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of or prevent cognitive disorder (Pa Sani people such as (Passani), pharmacology science trend (Trends Pharmacol.Sci.), 2004,25,618-625), epilepsy (Wo Hela people such as (Vohora), pharmacology, biological chemistry and behavior (Pharmacol.Biochem.Behav.), calendar year 2001,68,735-741), dysthymia disorders (Rui Zi-Jia Xiya people such as (Perez-Garcia), psychopharmacology (Psychopharmacol.), 1999 years, 142,215-220), attention deficit Attention Deficit Hyperactivity Disorder (ADHD) (Fox people such as (Fox), brain study of behaviour research (Behav.Brain Res.), 2002,131,151-61) and schizophrenia (Fox people such as (Fox), pharmacology and experimental therapeutic magazine (J.Pharmacol.Exp.Ther.), 2005 years, 313,176-190).Hereinafter sketch these indications.About out of Memory, referring to Li Yousi people such as (Leurs), comment naturally: drug discovery (Nat.Rev.Drug.Discov.), 2005 years, 4,107-120 and Wo Hela (Vohora), research medicine (Investigational Drugs), 2004,7, the comment of 667-673.Histamine H 3 receptor antagonists or inverse agonist also can be as novel methods of treatment (the Pa Sani people such as (Passani) of the cortex activated that recovers stupor or cerebral trauma patient, pharmacology science trend (Trends in Pharmacol.Sci.), 2004,25,618-625).
As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of or prevent epilepsy.Epilepsy (being commonly referred to the epileptic seizures illness) is a kind of chronic neuropathic shape that recurrent shows effect for no reason that is characterized as.With regard to its Activity Type, epileptic seizures can be called part (focal) or general.Partial seizures only relates to the local part of brain, and the generalized epilepsy outbreak relates to whole cortex.There is multiple different epilepsy syndromes, presents the combination of epileptic seizures type, typical age of onset, EEG result of study, treatment and the prognosis of himself uniqueness separately.Some common epileptic seizures syndromess comprise (for example) infantile spasms (west's syndrome (West syndrome)), the inattentive epilepsy disease of children and benign focal epilepsy of childhood's disease (the many epilepsys of optimum rowland (Benign Rolandicepilepsy)), teenager's lafora's disease disease, temporal epilepsy disease, frontal lobe epilepsy disease and Lin-Ge syndromes (Lennox-Gastaut syndrome).
The compounds of this invention can be used in combination with various known drugs.For instance, The compounds of this invention can prevent the medicine of epileptic seizures or reduction epileptic seizures frequency to use with one or more, and these medicines comprise: Carbamzepine (carbamazepine) (trade(brand)name Tegretol (Tegretol) commonly used), clobazam (clobazam) (sentil (Frisium)), clonazepam (clonazepam) (Ke Nuoping (Klonopin)), ethosuximide (ethosuximide) (Zarontin (Zarontin)), non-ammonia ester (felbamate) (non-crust appropriate (Felbatol)), prophenytoin (fosphenytoin) (uncommon happy) than (Cerebyx), flurazepam (flurazepam) (band that dormancy (Dalmane)), gabapentin (gabapentin) (pressing down stupid insane (Neurontin)), lamotrigine (lamotrigine) (happy life reaches (Lamictal)), Levetiracetam (levetiracetam) (Kai Pulan (Keppra)), oxcarbazepine (oxcarbazepine) (Qu Lai (Trileptal)), mephenytoin (mephenytoin) (methoin (Mesantoin)), phenylethyl barbituric acid (phenobarbital) (luminol,3-aminophthalic acid cyclic hydrazide (Luminal)), Phenytoin Sodium Salt (phenytoin) (dilantin (Dilantin)), lyrica (pregabalin) (Li Ruika (Lyrica)), primidone (primidone) (Primidone (Mysoline)), Sodium Valproate (Sodium Valproate (Epilim)), tiagabine (tiagabine) (gal is than bent (Gabitril)), topiramate (topiramate) (appropriate Thailand (Topamax)), valproate semisodium (De Packh spy (Depakote)), valproic acid (Sodium Valproate (Depakene), antiepilepsirin (Convulex)) and vigabatrin (vigabatrin) (vigabactrin (Sabril)).Usually use other medicines to end reactivity epileptic seizures (active seizure) or interruption epileptic seizures confusion; These medicines comprise diazepam (diazepam) (stable (Valium)) and lorazepam (lorazepam) (stable literary composition (Ativan)).The medicine that only is used for the treatment of intractable epileptic state comprises paraldehyde (paraldehyde) (paraldehyde (Paral)) and Sodital (pentobarbital) (Nai Bota (Nembutal)).
As mentioned above, histamine H 3 receptor antagonists or inverse agonist can or can be used in combination with other medicament as independent therapeutical agent.For instance, Wo Hela people such as (Vohora) shows effect (the Wo Hela people such as (Vohora) that histamine H 3 receptor antagonists can be used as anti-epileptic disease, anti-epileptic outbreak medicine and also show H3 receptor antagonist with the known antiepileptic drug of time effective dose of time effective dose, pharmacology, biological chemistry and behavior (Pharmacol.Biochem.Behav.), calendar year 2001,68,735-741).
Rui Zi-Jia Xiya people's (psychopharmacology (Psychopharmacol.) such as (Perez-Garcia), 1999,142,215-220) test histamine H3 receptor stimulant and antagonist are to the effect of the experiment mice model of anxiety disorder (overhead cross labyrinth (elevatedplus-maze)) and dysthymia disorders (forced swimming test (forced swimming test)).Although they find that described compound does not have remarkable effect to the anxiety disorder model, the H3 receptor antagonist has remarkable dose-dependent effects really in depression model.Therefore, histamine H 3 receptor antagonists or inverse agonist may have antidepressant effect.
Clinical depression is the sad or melancholy state that has developed into the degree of destroying individual social function and/or activities of daily living.Clinical depression invasion and attack colony about 16% occurs at least once in life at it.According to the World Health Organization (World Health Organization), clinical depression is the major cause of DB in the U.S. and other country at present, and anticipates that the year two thousand twenty will become the second largest reason (after heart disease) of DB in the world wide.
The compounds of this invention can be used in combination with various known drugs.For instance, The compounds of this invention can use with one or more present available medicines that can alleviate depressive symptom.These medicines comprise (for example): oxidase inhibitor (MAOI), for example Phenelzine (Nardil) or moclobemide (Moclobemide) (mana auspicious (Manerix)); Tricyclic antidepressants; Selective serotonin reuptake inhibitor (SSRI), for example fluoxetine (fluoxetine) (Prozac (Prozac)), paroxetine (paroxetine) (seroxat (Paxil)), escitalopram (escitalopram) (coming scholar general (Lexapro)) and Sertraline (sertraline) (Zoloft (Zoloft)); NRI, for example Reboxetine (reboxetine) (according to Qu Na (Edronax)); And thrombotonin-NRI (SNRI), for example Venlafaxine (venlafaxine) (speed is pleased (Effexor)) and duloxetine (duloxetine) (glad hundred reach (Cymbalta)).
As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of or prevent attention deficit Attention Deficit Hyperactivity Disorder (ADHD).Diagnostic and statistical manual-IV-TR (Diagnostic and Statistical Manualof Mental Disorders-IV-TR) according to mental illness, the developmental character illness of (in most of the cases before the 7 years old) Childhood that ADHD being a kind of coming across, it is characterized by the absent minded and/or undue activity-impulsive action of grow going up improper degree, and cause the infringement of one or more main vital movements (for example family, of the same generation, education, occupation, society or adaptive functions).Also may diagnose out ADHD in the Adulthood.
If be used for the treatment of the line drug main stimulant of ADHD, it be responsible for to be concentrated by stimulating, the brain area of attention and impulsion control works.Doping is treated feature and is generally undue active syndromes and is called contradiction effect (paradoxical effect) sometimes, but there is not real contradiction, reason is that stimulant activates brain and suppresses and self's mechanism, thereby allows the individual bigger self-control that has.Used stimulant comprises (for example) Methylphenidylacetate (selling with Ritalin (Ritalin), Ritalin SR and Ritalin LA), Ritalin (Metadate), Ritalin sustained release dosage (Metadate ER), methylphenidate hydrochloride (Metadate CD), absorbed (Concerta), the right Methylphenidylacetate (Focalin) of hydrochloric acid, the right Methylphenidylacetate slow releasing capsule (Focalin XR) of hydrochloric acid or the methylphenidate hydrochloride (Methylin) of reaching.Stimulant also comprises (for example): Amphetamine, for example dexamphetamine is sold with Dextroamphetamine, Dextroamphetamine spansule (Dexedrine Spansule), amphetamine and amphetamine salt mixture (Adderall XR) (trade name of the mixture of dexamphetamine and left-handed Amphetamine salt); Meth is sold with methyl amphetamine; Bupropion (bupropion); Dopamine HCL; And NRI, rich meaningful (Wellbutrin) sells with the trade(brand)name prestige.The non-stimulant substance that is used for the treatment of ADHD is atomoxetine (Atomoxetine) (thinking to reach (Strattera) sale to select), and it is a kind of NRI.Sometimes the other medicines that are used for ADHD comprise (for example) benzyl propyl benzene Isopropylamine (benzphetamine), protect clear-headed/Altay gram (Alertec)/modafinil and clonidine (clonidine).Recently be reported in the rat cub model of ADHD, histamine H 3 receptor antagonists the same with Methylphenidylacetate (Ritalin) at least effective (Chinese cock (Hancock) and Fox (Fox), the milestone of pharmacotherapy (Milestones in Drug Therapy), cloth Kaffirs section (Buccafusco) compiles, 2003).The compounds of this invention can be used in combination with various known drugs.For instance, The compounds of this invention can use with one or more medicines that is used for the treatment of ADHD and associated conditions.
As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for the treatment of or prevent schizophrenia.Schizophrenia is to describe to be characterized as real perception or to express infringement and the psychosis diagnosis of the mental illness of remarkable society or professional dysfunction.Experience untreated schizoid people and be characterized as displayed thinking chaotic and experience illusion or phonism usually.Although think that described illness mainly influences cognitive power, it also may cause the chronic problem about behavior and mood.Usually just schizophrenia is described in " positive " symptom and " feminine gender " symptom aspect.Positive symptom comprises illusion, phonism and the disturbance of thought, and is regarded as psychotic manifestation usually.Negative symptoms is because think it for the forfeiture of normal characteristic or ability or there is not so name, and comprises such as features such as flat, blunt or mechanical emotion and mood, flat, monotonous language and shortage power.Some schizophrenia models comprise the form of thought obstacle in the 3rd group and the difficulty (" entanglement syndromes ") of working out a scheme.
Typically use antipsychotics about a schizoid line pharmacological treatments.Think that antipsychotics only provides the sx of psychosis positive symptom.Newer atypical antipsychotics thing (for example leoponex (clozapine), risperidone (risperidone), olanzapine (olanzapine), Quetiapine (quetiapine), Ziprasidone (ziprasidone) and Aripiprazole (aripiprazole)) is better than older typicalness antipsychotics (for example chlorpromazine (chlorpromazine) and haloperidol (haloperidol)) usually because of its favourable side effect overview.Although the atypical antipsychotics thing is compared to less EPS of conventional antipsychotic drug deposits yields and tardive dyskinesia, but as if some medicaments in this class (especially olanzapine and leoponex) produce such as metabolism side effects such as weight increase, hyperglycemia and hypertriglyceridemias, should be taken into account this problem when selecting suitable pharmacotherapy.
Histamine H 3 receptor antagonists or inverse agonist can be used for the treatment of obesity (Chinese cock (Hancock), research medicine recent reviews (Curr.Opin.Investig.Drugs), 2003,4,1190-1197).The reduction appetite that the effect of neuronal histamine in ingestion of food determined many years and neuronal histamine release and/or signal transduction involve known amboceptor (for example leptin (leptin), pancreas opsonin (amylin) and Magainin (bombesin)) in the feed circulation on.In brain, the H3 acceptor involves in regulating hypothalamic histamine release.In addition, the histamine H 3 receptor mRNA that in situ hybridization research has disclosed in the rat brown adipose tissue expresses, and shows and regulates effect (the Ka Ersi Taide people such as (Karlstedt) who gives birth to heat, molecular cell neuroscience (Mol.Cell.Neurosci.), 2003,24,614-622).In addition, various clinical before in the obesity model research histamine H 3 receptor antagonists and its be illustrated in and can effectively reduce ingestion of food in the mouse, reduce body weight and reduce total body fat (total body fat) (Chinese cock people such as (Hancock), Europe pharmacology magazine (Eur.J.Pharmacol.), 2004,487,183-197).The most common medicine that is used for the treatment of obesity is sibutramine (sibutramine) (Reductil (Meridia)) and orlistat (orlistat) (orlistat (Xenical)), and both have limited effectiveness and significantly side effect for it.Therefore, need novel antiobesity agent, for example histamine H 3 receptor antagonists or inverse agonist.
Histamine H 3 receptor antagonists or inverse agonist also can be used for the treatment of air flue anaphylaxis (United States Patent (USP) the 5th, 217, No. 986; The 5th, 352, No. 707; With the 5th, 869, No. 479), comprise allergic rhinitis and nasal congestion.Allergic rhinitis is a large amount of crowds' of invasion and attack a common chronic disease.The latest analysis of histamine H 3 receptor being expressed outside in week by quantitative PCR disclose H3 receptor mrna great expression in human nasal mucosa (Wei Di people such as (Varty), European pharmacology magazine (Eur.J.Pharmacol.), 2004,484,83-89).In addition, in alleviating the cat model of nasal congestion, the significant nasal congestion of combination results of histamine H 3 receptor antagonists and H1 receptor antagonist chlorphenamine (chlorpheniramine) alleviates, and there is not adrenaline excitant visible hypertension effect (MacLeod people such as (McLeod), U.S.'s rhinology magazine (Am.J.Rhinol.), 1999,13,391-399).Therefore, histamine H 3 receptor antagonists or inverse agonist can use separately or be used in combination with treatment of allergic rhinitis and nasal congestion with the H1 receptor blocking.
Histamine H 3 receptor antagonists or inverse agonist have treatment treatment of pain potentiality (Medhurst, Walter Henry people such as (Medhurst), biological chemistry pharmacology (Biochemical Pharmacology), (2007), 73 (8), 1182-1194).
Medical composition
Another aspect of the present invention relates to medical composition, and it comprises one or more compound and one or more pharmaceutically acceptable supporting agents as described herein.Some embodiment relate to medical composition, and it comprises The compounds of this invention and pharmaceutically acceptable supporting agent.
Some embodiments of the present invention comprise a kind of method of making medical composition, and it comprises at least a compound according to any compound embodiment disclosed herein is mixed with pharmaceutically acceptable supporting agent.
Can prepare composite by any appropriate method, usually by with one or more active compounds and liquid or finely powdered solid carriers or both with required ratio uniform mixing and follow (in case of necessity) and the gained mixture is configured as desired shape prepares.
Such as conventional excipients such as tackiness agent, weighting agent, acceptable wetting agent, system ingot lubricant and disintegrating agent can be used for tablet and capsule with carry out oral throwing with.Be used for oral throwing and liquid preparation may be solution, emulsion, water-based or oily suspensions and syrupy form.Perhaps, oral preparations may be the form of dry powder, and it is water or another kind of suitable liquid mediator reprovision before use.Can will add in the liquid preparation such as suspension agent or other additive such as emulsifying agent, non-aqueous mediator (comprising edible oil), sanitas and seasonings and tinting material etc.Can carry out filter sterilised by The compounds of this invention being dissolved in the suitable liquid mediator and, then fill and seal suitable bottle or ampoule and prepare non-through the intestines formulation to solution.These just under well-known some examples that are used for preparing numerous proper methods of formulation in technical fields.
Can use the well-known technology of those skilled in the art that The compounds of this invention is deployed into medical composition.Under known suitable pharmaceutically acceptable supporting agent except that described herein in the technical field; For example referring to Lei Mingdun (Remington), the pharmacy science with put into practice (The Science and Practice of Pharmacy), the 20th edition,, Li Pingkedi WILLIAMS-DARLING Ton-(the Lippincott Williams of Louis Wilkins press in 2000; Wilkins), (editor: Jie Naluo people such as (Gennaro)).
Although for being used for prevention or treatment, The compounds of this invention might be in another purposes can former chemical substance or pure chemistry material form throw with, but preferably present compound or activeconstituents with pharmaceutical formulation or the composition forms that further comprises pharmaceutically acceptable supporting agent.
Therefore the present invention further provides pharmaceutical formulation, it comprises The compounds of this invention or its pharmaceutically acceptable salt or derivative and one or more its pharmaceutically acceptable supporting agent and/or prevention composition.Can be compatible with other composition of composite and excessively do not endanger on its recipient's the meaning, described supporting agent should be " acceptable ".
Pharmaceutical formulation comprise be suitable for per os, per rectum, intranasal, part (comprising), transvaginal through cheek with through the hypogloeeis or non-through intestines (comprising intramuscular, subcutaneous and intravenously) throw and pharmaceutical formulation or be suitable for by suck, be blown into or by transdermal patch throw and the pharmaceutical formulation of form.Transdermal patch distributes medicine for absorption with controllable rate by present medicine with effective means under the situation of drug degradation minimum.Usually, transdermal patch comprises backing layer, the single pressure-sensitive tackiness agent of impenetrability and has the removable protective layer of release liner.One of ordinary skill in the art will understand and understand the technology that is suitable for making required effective transdermal patch based on technician's needs.
Therefore The compounds of this invention and conventional adjuvant, supporting agent or thinner can be placed pharmaceutical formulation form and its unit dosage, and in this form, can following form use: such as solids such as tablet or filled capsules, or such as solution, suspension, emulsion, elixir, gel or be filled with the liquid such as capsule of described material, all are used to orally use; Suppository form, be used for rectum throw with; Or the sterile injectable solution form, non-ly use being used for through intestines (comprising subcutaneous).These medical compositions and its unit dosage may comprise the conventional ingredient of conventional ratio, wherein have or do not have other active compound or composition, and these unit dosage may contain the activeconstituents of any suitable effective amount of expection dosage range every day that is equivalent to the desire use.
For oral throwing with, medical composition may be the form of (for example) tablet, capsule, suspension or liquid.Preferably medical composition is made the form of the dose unit that contains the specified quantitative activeconstituents.The example of these dose units is capsule, tablet, powder, granule or suspension, wherein has such as conventional additives such as lactose, mannitol, W-Gum or yam starchs; Have such as tackiness agents such as crystalline cellulose, derivatived cellulose, gum arabic, W-Gum or gelatin; Have such as disintegrating agents such as W-Gum, yam starch or Xylo-Mucines; And have such as lubricants such as talcum powder or Magnesium Stearates.Also can throw and activeconstituents by injecting with composition forms, wherein, for example salt solution, dextrose or water can be used as suitable pharmaceutically acceptable supporting agent.
The compounds of this invention or its solvate or physiologic function derivative can be as the activeconstituentss in the medical composition, especially as histamine H 3 receptor modulators.Term " activeconstituents " defines and plans to represent to provide the component of the medical composition of main pharmacotoxicological effect in the content of " medical composition ", in contrast, will think that generally " non-active ingredient " do not provide medical benefit.
When using The compounds of this invention, dosage can change in broad range, and as the doctor use always also knownly, under each individual instances, will regulate dosage according to individual state.Dosage depends on the character and the seriousness of (for example) desire treatment disease; Patient's situation; Compound used therefor; Or not acute or chronic disease state are not treated or do not prevent; Or except that The compounds of this invention, whether throw and other active compound.Representative dosage of the present invention includes, but is not limited to about 0.001mg and arrives about 500mg, 0.001mg to about 5000mg, about 0.001mg to about 2500mg, about 0.001mg to about 1000mg, 0.001mg and arrive about 250mg, about 0.001mg and arrive about 50mg and about 0.001mg arrives about 25mg to 100mg, about 0.001mg.Especially when thinking the relatively large amount of needs, in one day, can throw and a plurality of dosage, for example 2,3 or 4 dosage.Decide and when patient's doctor or paramedic think fit, have necessity and depart from described dosage up or down herein on individuality.
The amount that is used for the treatment of required activeconstituents or its active salt or derivative not only will change about selected specific salts, and will change, and at last will be according to attending doctor or clinician's judgement about the symptom character of dosing way, desire treatment and patient's age and situation.In general, the those skilled in the art understands the in vivo data how will obtain and is extrapolated to another system (for example mankind) in model system (normally animal model).In some cases, these extrapolations may be just based on the weight ratio of animal model and another system (for example Mammals is preferred human), yet, more generally be that these extrapolations are not simply based on body weight, but comprise multiple factor.Representative factor comprises patient's build, age, body weight, sex, diet and medical condition; Severity of disease; Dosing way; Pharmacology is considered, the for example activity of used specific compound, effect, pharmacokinetics and toxicology overview, whether utilize drug delivery system, whether treat or do not prevent, or except that The compounds of this invention, whether throw with other active compound and as the part of drug regimen over against acute or chronic disease state.Select dosage regimen according to aforesaid multiple factor with compound of the present invention and/or composition therapeuticing disease situation.Therefore, used actual dosage regimen can change in broad range and therefore may depart from preferred dosage regimen, and those skilled in the art will realize that dosage and dosage regimen outside these typical ranges can be used for method of the present invention after tested and in due course.
Required dosage can be rendered as aptly single dose or with appropriate time throw at interval and the divided dose form, for example two, three of every days, four or more sub-dosage.Sub-dosage itself can further be subdivided into the dispensing at (for example) a plurality of discrete loose intervals.Especially when thinking that it is suitable throwing with relatively large amount, per daily dose can be divided into some parts (for example 2,3 or 4 parts) throw with.Decide on individual behavior, in the time of suitably, dosage has necessity and departs from described per daily dose up or down.
Can be multiple orally and non-throw and The compounds of this invention through the intestines formulation.The those skilled in the art will recognize obviously that following formulation may comprise the pharmaceutically acceptable salt as the The compounds of this invention of active ingredient or The compounds of this invention.
In order to prepare medical composition by The compounds of this invention, the selection of suitable pharmaceutically acceptable supporting agent may be solid, liquid or both mixtures.But the solid form preparation comprises powder, tablet, pill, capsule, flat jelly, suppository and dispersible granule.Solid carriers may be one or more materials, and it also may serve as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or capsule closure material.
In powder, supporting agent is the finely powdered solid, and it is the mixture with the finely powdered active ingredient.
In tablet, active ingredient mixed with proper ratio with the supporting agent with necessary adhesive capacity and be pressed into desired shape and size.
Powder and tablet can contain the active compound of different weight percentage amount.Representativeness amount in powder or the tablet can contain 0.5% to about 90% active compound; Yet when the technician need be in the amount outside this scope if can knowing.The suitable supporting agent that is used for powder and tablet is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil or the like.Terms " formulation " plans to comprise active compound and composite as the capsule closure material of supporting agent, thereby provides the active ingredient that wherein contains or do not contain supporting agent to be surrounded by supporting agent and therefore mutual associating capsule.Similarly, comprise flat jelly and lozenge.Tablet, powder, capsule, pill, flat jelly and lozenge can be suitable for oral throwing and solid form use.
Be preparation suppository, at first make low melt wax (for example mixture of glycerin fatty acid ester or theobroma oil) fusion and active ingredient is evenly dispersed in wherein by stirring.Then the fused homogenizing mixture is poured in the mould of suitable size, made its cooling, thereby and solidify.
Be suitable for that vagina is thrown and composite can be rendered as the form of hysterophore, tampon, emulsifiable paste, gel, paste, foams or spraying, it also contains just like being known as suitable supporting agent in the affiliated technical field except that containing activeconstituents.
Liquid form preparation comprises solution, suspension and emulsion, for example water or water-propylene glycol solution.For instance, non-ly can be formed in solution form in the polyoxyethylene glycol aqueous solution through allotment through the enteral administration liquid preparation.Can use suitable dispersion agent or wetting agent and suspension agent to allocate injectable formulation according to known technology, for example aseptic injectable water-based or oily suspensions.Sterile injectable preparation also may be in nontoxic non-sterile injectable solution or suspension in intestines acceptable diluent or solvent, for example solution in 1,3 butylene glycol.Operable acceptable mediator and solvent comprise water, Ringer's solution (Ringer ' s solution) and etc. open sodium chloride solution.In addition, use aseptic fixed oil as solvent or suspension medium usually.For this purpose, any non-irritating fixed oil be can use, synthetic property direactive glyceride or two glyceryl ester comprised.In addition, can be used for preparing injection such as lipid acid such as oleic acid.
Therefore The compounds of this invention can present to be used for non-the throwing with (for example by injection, for example injecting (bolusiniection) or continuous infusion) and the unit dosage form that can be added with in ampoule, pre-filled syringe, small volume infusion or the multi-dose container of sanitas through intestines through allotment.Medical composition can adopt such as forms such as the suspension in oiliness or aqueous vehicles, solution or emulsions, and may contain such as blenders such as suspension agent, stablizer and/or dispersion agents.Perhaps, activeconstituents may be by the aseptic separation of sterile solid or the powder type by obtaining from the solution freeze-drying, uses suitable mediator (for example aseptic pyrogen-free matter water) to carry out reprovision before use.
Can be by with solubilization of active ingredient or be suspended in the water and add suitable tinting material, seasonings, stablizer and thickening material on demand and prepare the water-based composite that is suitable for orally using.
Can prepare the waterborne suspension that is suitable for orally using in the water that contain viscous substance by the finely powdered active ingredient is dispersed in, described viscous substance is for example natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or other well-known suspension agent.
Also comprise the solid form preparation, plan before being about to use, to convert it into liquid form preparation with carry out oral throwing with.These liquid forms comprise solution, suspension and emulsion.Except that containing active ingredient, these preparations also may contain tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent or the like.
About the part of epidermis is thrown with, The compounds of this invention can be deployed into ointment, emulsifiable paste or lotion form, or be deployed into the transdermal patch form.
Can be for example under the situation that adds suitable thickening and/or jelling agent use or oleaginous base allocate ointment and emulsifiable paste.Can use or oleaginous base allocate lotion and its general emulsifying agent, stablizer, dispersion agent, suspension agent, thickening material or tinting material that also will contain one or more.
Be suitable in mouth local throw and composite comprise: lozenge, it comprises the promoting agent in the flavoured base that is generally sucrose and gum arabic or tragacanth; Lozenge, it comprises such as the activeconstituents in the inert bases such as gelatin and glycerine or sucrose and gum arabic; And collutory, it comprises the activeconstituents in the suitable liquid carrier.
Solution or suspension are (for example to use dropper, suction pipe or atomizer) by conventional methods to be applied directly to nasal cavity.Can single dose or the multiple doses form composite is provided.Under the latter event of dropper or suction pipe, this can realize by throwing with the solution or the suspension of suitable pre-determined volume to the patient.Under the situation of atomizer, this can for example realize by means of metered spray pump.
Also can by means of the aerosol composite realize to the throwing of respiratory tract with, activeconstituents provides in the compression wrap with suitable propelling agent in the aerosol composite.If The compounds of this invention or the medical composition that comprises The compounds of this invention be with aerosol (for example nose aerosol) form or by suck throw with, this can for example use atomizer, spraying gun, pump spraying gun, suction apparatus, metered dose inhaler or Diskus to implement so.Can prepare by the well-known method of those skilled in the art and be used for the medical form of aerosol form throwing with The compounds of this invention.About its preparation, for instance, can use solution or the dispersion liquid of The compounds of this invention in water, water/alcohol mixture or suitable salt brine solution, it uses typical additives (for example benzylalcohol) or other suitable sanitas, the absorption enhancer that is used to increase bioavailability, solubilizing agent, dispersion agent and other reagent; And propelling agent commonly used suitably the time, for example comprise carbonic acid gas, CFC (for example Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane); Or the like.Aerosol also may contain such as tensio-active agents such as Yelkin TTS aptly.Can control the dosage of medicine by metering valve is provided.
Be intended for use to respiratory tract throw and composite (comprising composite in the nose) in, compound generally will have for example 10 microns or 10 microns following magnitudes than small grain size.Can obtain this granularity by known mode in the affiliated technical field (for example by micronization).When needing, can use the composite of the slowly-releasing that is suitable for providing activeconstituents.
Perhaps, can provide activeconstituents by dry powder form, for example, compound is such as the powdered mixture in lactose, starch, the starch derivative suitable powder matrix such as (for example HYDROXY PROPYL METHYLCELLULOSE and polyvinylpyrrolidones (PVP)).The powder supporting agent will form gel easily in nasal cavity.Powder composition can present by unit dosage form, for example gelatine capsule or cartridge case, or can be by means of sucker from wherein throwing the Blister Package with powder.
Pharmaceutical preparation preferably is unit dosage.In this form, preparation is subdivided into the unitary dose of the active ingredient that contains appropriate amount.Unit dosage can be packaged preparation, and described packing contains the preparation of discrete magnitude, for example package troche, capsule and the powder in bottle or ampoule.In addition, unit dosage can be capsule, tablet, flat jelly or lozenge itself, or it can be any these unit dosage that are packaged form of proper number.
Be used for oral throwing and tablet or capsule and be used for that intravenously is thrown and liquid be preferred composition.
The compounds of this invention can randomly exist with pharmaceutically acceptable salt form, and described salt comprises the pharmaceutically acceptable acid salt by pharmaceutically acceptable non-toxic acid (comprising mineral acid and organic acid) preparation.Representative acid includes, but is not limited to acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, dichloro acetic acid, formic acid, FUMARIC ACID TECH GRADE, gluconic acid, L-glutamic acid, urobenzoic acid, Hydrogen bromide, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, oxysuccinic acid, amygdalic acid, methanesulfonic, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, Succinic Acid, sulfuric acid, tartrate, oxalic acid, tosic acid or the like, medical science magazine (Journal ofPharmaceutical Sciences) for example, those listed pharmaceutically acceptable salt among the 66:1-19 (1977); The full text of described document is incorporated herein by reference.
Acid salt can be used as the synthetic direct product of compound and obtains.In alternative method, free alkali can be dissolved in the suitable solvent that contains suitable acid, and by evaporating solvent or otherwise separated salt and solvent are isolated salt.Use the known method of those of skill in the art, for example medical solid polymorphism (Polymorphism inPharmaceutical solids, edit by Harry G. Britten (Harry G.Brittain), Marseille Er Daike (MarcelDekker), New York (New York), 1999, it was incorporated herein by reference in full) described in method, The compounds of this invention can form solvate with the standard low molecular weight solvent.
The compounds of this invention can change into " prodrug ".Under term " prodrug " is meant in the technical field compound of known particular chemical base group modification and when throwing these groups experience bio-transformations so that parent compound to be provided with in individuality the time.Therefore can think that prodrug is to contain one or more special-purpose nontoxicity protecting groups of using in of short duration mode to change or to eliminate the The compounds of this invention of certain compound characteristic.One general aspect in, utilize " prodrug " method to promote oral absorption.Detailed argumentation is provided in T. bung (T.Higuchi) and V. Si Tela (V.Stella), as the prodrug (Prodrugs as Novel Delivery Systems) of novel transfer system, the 14th volume of A.C.S. collection of thesis series (Symposium Series); And the biological reversibility supporting agent in the medicinal design (Bioreversible Carriersin Drug Design), Edward B. Luo Shi (Edward B.Roche) compiles, American Pharmaceutical Association and Pei Geman press (American Pharmaceutical Association and Pergamon Press), in 1987, described two kinds all is to be incorporated herein in full by reference with reference to document.
Some embodiments of the present invention comprise that a kind of manufacturing is used for the method for the medical composition of " combination treatment ", and it comprises at least a compound and at least a known as described herein medical agent and pharmaceutically acceptable supporting agent according to any compound embodiment disclosed herein is mixed together.
It should be noted that when utilizing histamine H 3 receptor modulators as the activeconstituents in the medical composition, these materials are not intended to only be used for the mankind, but are used for other non-human mammal yet.In fact, the latest developments of animal health healthcare field require to consider use such as histamine H 3 receptor modulators isoreactivity agent to treat the diseases related or illness of H3 of domestic animal (for example cat and dog) and other domestic animal (for example ox, chicken, fish etc.).Believe that easily one of ordinary skill in the art understand the effectiveness of these compounds under these situations.
Other effectiveness
Another object of the present invention relates to through radiolabeled The compounds of this invention, it not only will be applicable to radiological imaging, and will be applicable in vitro and in vivo analyze, differentiate histamine H 3 receptor ligands with the histamine H 3 receptor in location and the quantitative tissue sample (comprising the mankind) and by the inhibition combination of radio-labeled compound.Another object of the present invention is to develop the novel H3 receptor assay that comprises these radio-labeled compounds.
The present invention is contained through isotope-labeled The compounds of this invention." isotopic labeling " or " radio-labeling " compound is identical with compound disclosed herein, but one or more atoms are different from the atomic substitutions of modal atomic mass of occurring in nature or total mass number or the compound of replacement through atomic mass or total mass number.The suitable radionuclide that can incorporate in the The compounds of this invention includes, but is not limited to
2H (also being write deuterium as D),
3H (also being write tritium as T),
11C,
13C,
14C,
13N,
15N,
15O,
17O,
18O,
18F,
35S,
36Cl,
82Br,
75Br,
76Br,
77Br,
123I,
124I,
125I and
131I.The radionuclide of incorporating in the radio-labeled compound of the present invention will be decided on the application-specific of described radio-labeled compound.For instance, in vitro histamine H 3 receptor mark and competition analysis, and have
3H,
14C,
82Br,
125I,
131I or
35The compound of S generally will be the most suitable.Use for radiological imaging,
11C,
18F,
125I,
123I,
124I,
131I,
75Br,
76Br or
77Br generally will be the most suitable.
Should be appreciated that " radio-labeling " or " tagged compound " is and formula (Ia) compound of at least one radionuclide is arranged; In certain embodiments, radionuclide be selected from by
3H,
14C,
125I,
35S and
82The group that Br forms.Some is in isotope-labeled The compounds of this invention is applicable to that compound and/or substrate tissue distribution are analyzed.In certain embodiments, radionuclide
3H and/or
14The C isotropic substance is applicable in these researchs.In addition, through higher isotope (deuterium for example, promptly
2H) replacement can provide by some the treatment advantage that produces than greater metabolic stability (for example, the dosage demand of the in vivo transformation period of increase or reduction) and therefore can be first-selection in some cases.Generally can by follow with graphic and example hereinafter in the similar program that discloses, use through isotope-labeled reagent replacement without isotope-labeled reagent, prepare through isotope-labeled The compounds of this invention.Hereinafter discuss other synthetic method that is suitable for.In addition, should be appreciated that all represented atoms can be the most common isotropic substance or the rarer radio isotope or the non radioactive isotopes of these atoms in the The compounds of this invention.
Incorporate radio isotope into synthetic method in the organic compound can be applicable to The compounds of this invention and well-known in affiliated technical field.These synthetic methods (for example the tritium of activity level being incorporated in the target molecule) are as follows:
A. carrying out catalytic reduction-this program with tritium gas produces the high specific acitivity product usually and needs halogenation or unsaturated precursor.
B. use boron hydrogen [
3H] to change sodium reduction-this program quite cheap and need contain precursor such as aldehyde, ketone, lactone, ester or the like reducible functional group.
C. use hydrogen [
3H] change lithium aluminium reducing-this program provides and have the almost product of theoretical specific activity.It also needs to contain the precursor such as aldehyde, ketone, lactone, ester or the like reducible functional group.
D. tritium gas exposure mark-this program is included in the precursor that contains exchangeable protons is exposed in the tritium gas.
E. use methyl iodide [
3H] carry out N-methylate-this program be generally used for by with the high specific acitivity methyl iodide (
3H) handle suitable precursor prepare O-methyl or N-methyl (
3H) product.This method generally allows than high specific acitivity, for example about 70-90Ci/mmol.
With activity level
125The synthetic method that I incorporates in the target molecule comprises:
A. Sang De mayer (Sandmeyer) reaction and similar reaction-this program are converted into arylamine or assorted arylamine such as diazonium salts such as a tetrafluoro borates, and use Na subsequently
125I be converted into through
125The compound of I mark.Described program by Zhu G-D (Zhu, G-D.) and the colleague be reported in organic chemistry magazine (J.Org.Chem.), 2002,67, among the 943-948.
B. the ortho position of phenol
125I iodate-this program makes to be incorporated on the ortho position of phenol
125I, as Collier, Jeremy T.L. (Collier, T.L.) and colleague at tagged compound radiopharmaceuticals magazine (J.Labelled Compd.Radiopharm.), 1999,42, report among the S264-S266.
C. aryl bromide and heteroaryl bromine with
125I exchanges-and this method generally is a two-step approach.The first step is to have trialkyltin halogenide or six alkyl, two tin [(CH for example
3)
3SnSn (CH
3)
3] situation under to use the reaction of (for example) Pd catalytic type [be Pd (Ph
3P)
4] or by lithium aryl or heteroaryl lithium aryl bromide or heteroaryl bromine are converted into corresponding trialkyltin intermediate.Representative program by Li Basi M.-D. (Le Bas, M.-D.) and the colleague be reported in tagged compound radiopharmaceuticals magazine (J.Labelled Compd.Radiopharm.), calendar year 2001,44, among the S280-S282.
Histamine H 3 receptor compound through radiolabeled formula (Ia) can be used for the screening analysis with discriminating/assessment compound.In general, can assess the ability of its reduction " through radiolabeled formula (Ia) compound " and H3 receptors bind to the compound (being test compounds) that synthesizes recently or differentiate.Therefore, test compounds is directly related with its binding affinity with the ability that " through radiolabeled formula (Ia) compound " competition combines histamine H 3 receptor.
The compounds of this invention through mark combines with histamine H 3 receptor.In one embodiment, has IC through tagged compound less than about 500 μ M
50, in another embodiment, have IC less than about 100 μ M through tagged compound
50, in another embodiment, have IC less than about 10 μ M through tagged compound
50, in another embodiment, have IC less than about 1 μ M through tagged compound
50, and in another embodiment, have IC less than about 0.1 μ M through the mark inhibitor
50
Especially according to comment of the present invention, other purposes of the acceptor that discloses and method will become apparent to those of ordinary skill in the art.
To recognize that the step of the inventive method need not to carry out any specific times or carries out with any particular order.After studying following example of the present invention, other purpose of the present invention, advantage and novel feature will become apparent to those of ordinary skill in the art, and described example is intended as explanation and does not plan to be construed as limiting.
Example
Example 1: The compounds of this invention synthetic
The illustrative of The compounds of this invention is synthetic to be illustrated in Fig. 1 in Fig. 7, and wherein symbol has the used identical definition with the present invention in the whole text.
It is synthetic with it to further specify compound of the present invention by following example.Provide following example to further specify the present invention, but be not the details that limit the invention to these examples.This paper above and hereinafter described compound be to name according to CS ChemDraw Ultra 7.0.1 version, AutoNom 2.2 editions.Use popular name in some cases and should be appreciated that these popular names will be for being appreciated by one of skill in the art that.
Chemistry: with being equipped with 4 to endorse the Varian mercury Vx-400 (Varian MercuryVx-400) of automatically switch probe and z gradient or be equipped with four nuclear probe (QNP; Quad Nucleus Probe) or the reverse (BBI in broadband; Broad BandInverse) and the Brooker A Wangsi-400 of z gradient (Bruker Avance-400) write down proton magnetic resonance (PMR) (
1HNMR) spectrum.About providing chemical shift with PPM (ppm) with residual solvent signal for referencial use.Use following NMR abbreviation: s=is unimodal, d=doublet, t=triplet, q=quartet, the m=multiplet, br=broad peak, the doublet of dt=triplet, the triplet of td=doublet, the doublet of dd=doublet, the doublet of the doublet of ddd=doublet.Use Smith's synthesizer
TM(Smith Synthesizer
TM) or auspicious this optimizer of em
TM(EmrysOptimizer
TM) (individual chemical company (Personal Chemistry)) implement microwave irradiation.Use silica gel 60F
254(Merck (Merck)) carries out thin-layer chromatography (TLC), (water graceful (Whatman)) is prepared type thin-layer chromatography (preparation type TLC) with PK6F silica gel 60A 1mm plate, and uses Kinsey Ji 60 (Kieselgel 60) 0.063-0.200mm (Merck (Merck)) to carry out column chromatography with silicagel column.Under reduced pressure evaporate with step fine jade (Buchi) Rotary Evaporators.During filtering, palladium uses diatomite
LCMS specification: HPLC pump: LC-10AD VP, Tianjin, island company (Shimadzu Inc.); HPLC central controller: SCL-10A VP, Tianjin, island company (Shimadzu Inc); UV detector: SPD-10A VP, Tianjin, island company (ShimadzuInc); Self-actuated sampler: CTC HTS, PAL, sharp general science (Leap Scientific); Mass spectrograph: API 150EX has turbine ionspray source (Turbo Ion Spray source), u.s.a. applied biosystem company/Meng Disisaikesi company (AB/MDS Sciex); Software: analyst 1.2 (Analyst 1.2).
Example 1.1: preparation intermediate (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide
Steps A: preparation intermediate methanesulfonic 4-bromobenzene ethyl ester
(38.9g 193mmol) is dissolved among the DCM (193mL) with 4-bromobenzene ethanol.Add triethylamine (40.4mL, 290mmol) and mixture is cooled off in ice bath.By feed hopper dropwise add methane sulfonyl chloride (18mL, 232mmol).Remove ice bath and mixture was stirred 30 minutes.Reaction mixture with DCM (200mL) dilution, with 1M HCl (each 100mL) washed twice, is then used salt solution, saturated sodium bicarbonate and salt water washing.Organic phase is also filtered through dried over sodium sulfate.Under reduced pressure remove solvent, obtain the title compound (54.0g) of quantitative yield.
1H NMR(400MHz，CDCl
3)δppm 2.89(s，3H)，3.02(t，J＝6.82Hz，2H)，4.40(t，J＝6.82Hz，2H)，7.03-7.17(m，2H)，7.43-7.47(m，2H)。
Step B: preparation intermediate (R)-1-(4-bromobenzene ethyl)-2-crassitude
(12.2g 43.8mmol) is dissolved in the acetonitrile (88mL) with methanesulfonic 4-bromobenzene ethyl ester.Add yellow soda ash (6.04g, 57.0mmol), then add (R)-(-)-2-crassitude (4.48g, 52.6mmol).Reaction mixture is warmed up to 80 ℃ and stirred overnight.Yellow soda ash is filtered and under reduced pressure removes solvent.Thick resistates is suspended in the ethyl acetate (about 200mL) once more, with 1M HCl (75mL) extraction.With 1M HCl (each 30mL) ethyl acetate is extracted three times again.HCl is laminated and and make it be alkalescence (pH value is about 10) by adding yellow soda ash.Extract alkaline water layer with DCM (100mL).50% sodium hydroxide of 1mL is added in the water layer, use DCM (each 50mL) subsequently its extraction three times.DCM is also laminated, through Na
2SO
4Dry also filtration.Under reduced pressure remove solvent, obtain yellow oil (10.2g, 87% thick productive rate).By with ethyl acetate, then the silicon-dioxide column chromatography with the 0-10%MeOH elution in the ethyl acetate is further purified thick oily matter, obtains being the title compound (8.85g, 75%) of light yellow oily.C
13H
18The accurate mass calculated value of BrN: 267.1, experimental value: LCMS m/z=268.0 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.15 (d, J=6.06Hz, 3H), 1.37-1.53 (m, 1H), and 1.73-1.86 (m, 2H), 1.94-2.07 (m, 1H), and 2.21-2.35 (m, 2H), 2.35-2.48 (m, 1H), and 2.68-2.91 (m, 2H), 2.98-3.11 (m, 1H), and 3.18-3.29 (m, 1H), 7.14-7.20 (m, 2H), and 7.38-7.48 (m, 2H).
Step C: preparation intermediate (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide
(2.16g 8.04mmol) is dissolved among the THF (20mL) with (R)-1-(4-bromobenzene ethyl)-2-crassitude under argon gas.Reaction mixture is cooled to-78 ℃ and slowly add n-Butyl Lithium (the 1.6M hexane solution, 6.53mL, 10.4mmol).Stir after 90 minutes, and the adding triisopropyl borate ester (7.42mL, 32.1mmol).To be reflected at-78 ℃ kept 2 hours down.Make it be warmed up to room temperature and stirred 1.5 hours.1M HCl with 40mL makes muddy reaction mixture stopped reaction.Under reduced pressure remove THF.With 50% sodium hydroxide make remaining aqueous solution be alkalescence (pH value for about 8) and with ethyl acetate (each 50mL) with its extracting twice, and extract three times with DCM (each 50mL).Will be through merging organism through MgSO
4Drying is filtered and is concentrated, and obtains the yellow foam of 1.70g.With foam Et
2(2 * 20mL) wet-millings, and dry under high vacuum obtain being the title compound (1.19g, 64% productive rate) of light yellow solid shape to O.C
13H
20BNO
2The accurate mass calculated value: 233.2, experimental value: LCMS m/z=234.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.25 (d, J=6.32Hz, 3H), 1.49-1.61 (m, 1H), 1.80-1.97 (m, 2H), 2.04-2.18 (m, 1H), 2.61-2.74 (m, 2H), 2.76-2.98 (m, 3H), 3.19-3.45 (m, 2H), 7.16 (d, 2H), 7.48-7.62 (m, 2H).
Example 1.2: preparation 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-methyl acetate (compound 19)
Steps A: preparation intermediate 2-biphenyl-4-base-ethanol
Under 0 ℃ by the biphenylacetic acid of feed hopper in containing THF (250mL) (20.0g, add in 1000mL round-bottomed flask 94.2mmol) borine THF complex compound (240mL, 240mmol).Then reaction being heated to 65 ℃ reaches 3 hours and then is cooled to 0 ℃.With the slow stopped reaction of MeOH (250mL) and concentrated.With product with EtOAc (500mL) dilution and with 1M HCl (200mL), saturated NaHCO
3(200mL) and salt solution (200mL) washing.With organism through MgSO
4Drying is filtered also and is concentrated, the title compound (18.0g, 96% productive rate) of the solid state that obtains being white in color.
1H NMR(400MHz，CDCl
3)δppm 2.92(t，J＝6.44Hz，2H)，3.91(t，J＝6.57Hz，2H)，7.29-7.37(m，3H)，7.40-7.47(m，2H)，7.52-7.61(m，4H)。
Step B: preparation intermediate methanesulfonic 2-biphenyl-4-base-ethyl ester
2-biphenyl-4-base-ethanol in containing DCM (50mL) (5.00g, add in 250mL round-bottomed flask 25.2mmol) triethylamine (3.52mL, 25.2mmol) and methylsulfonyl chloride (2.16mL, 27.7mmol).Make it be warmed up to 25 ℃-30 ℃ of following stirrings and through 2 hours in this mixture.Dilute with the reactant filtration and with EtOAc (100mL).With this material water (50mL), 1M HCl (50mL), saturated NaHCO
3(50mL) and salt solution (50mL) washing.With organism through MgSO
4Drying is filtered and is concentrated, and obtains being the title compound (5.93g, 85% productive rate) of creamy white solid state.
1H NMR(400MHz，CDCl
3)δppm 2.89(s，3H)，3.11(t，J＝6.82Hz，2H)，4.46(t，J＝6.95Hz，2H)，7.29-7.34(m，2H)，7.34-7.38(m，1H)，7.41-7.47(m，2H)，7.54-7.60(m，4H)。
Step C: preparation intermediate (R)-1-(2-biphenyl-4-base-ethyl)-2-methyl-tetramethyleneimine
In the 250mL three neck round-bottomed flasks that are equipped with condenser, pack into yellow soda ash in the acetonitrile (30mL) (14.6g, 137.4mol) and (R)-2-methyl-pyrrolidine hydrochloride (5.57g, 45.8mmol).Mixture was stirred 10 minutes down at 25 ℃, and the methanesulfonic 2-biphenyl-4-base-ethyl ester in the adding acetonitrile (50mL) (14.5g, 52.7mmol).Follow mixture heating up to refluxing and stirring 16 hours.Reactant is filtered and concentrates, obtain dark-brown oily matter.(4 * 25mL) extract in EtOAc (125mL) and with 1M HCl with this substance dissolves.Make it be alkalescence with the water layer merging and by adding 50%NaOH (20mL).(7 * 25mL) extractions merge organic layer, through Na with DCM with water layer
2SO
4Drying is filtered and is concentrated.(hundred special base (Biotage) post 65M 2%-20%MeOH/DCM) with the crude product mixture purifying, obtain being orange buttery title compound (10.1g, 82%) by column chromatography.C
19H
23The accurate mass calculated value of N: 265.2, experimental value: LCMS m/z=266.1 (M+H
+);
1H NMR (400MHz, CDCl
3) δ ppm 1.13 (d, J=6.06Hz, 3H), 1.40-1.51 (m, 1H), and 1.66-1.78 (m, 1H), 1.78-1.88 (m, 1H), and 1.88-1.99 (m, 1H), 2.21 (q, J=8.84Hz, 1H), 2.28-2.39 (m, 2H), 2.79-2.94 (m, 2H), 3.07 (td, J=11.24,6.06Hz, 1H), 3.27 (dt, J
1=8.65, J
2=2.65Hz, 1H), 7.29 (d, J=8.34Hz, 2H), 7.31-7.35 (m, 1H), 7.38-7.46 (m, 2H), 7.49-7.54 (m, 2H), 7.55-7.62 (m, 2H).
Step D: preparation intermediate 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-SULPHURYL CHLORIDE
(0.703g 2.65mmol) is dissolved among the DCM (10mL) and is cooled to 0 ℃ with (R)-1-(2-biphenyl-4-base-ethyl)-2-methyl-tetramethyleneimine in the 100mL round-bottomed flask.Dropwise added through 10 minutes chlorsulfonic acid among the DCM (10mL) (1.76mL, 26.5mmol).Reactant was stirred 3 hours, slowly be warmed up to 25 ℃ simultaneously.By dropwise adding 50% saturated NaHCO
3Ice-cold solution (10mL) in come stopped reaction, add other ice and make solution keep ice-cold.Dilute this material and separate each layer with DCM (20mL).With DCM (2 * 40mL) aqueous layer extracted.Will be through merging organism through Na
2SO
4Drying is filtered and is concentrated, and obtains being the title compound (0.74g, 74%) of yellow solid shape.C
19H
22NO
2The accurate mass calculated value of S: 363.1, experimental value: LCMS m/z=364.1 (M+H
+);
1H NMR (400MHz, DMSO-d
6) δ ppm 1.21 (d, J=7.07Hz, 0.3H), 1.40 (d, J=6.57Hz, 2.7H), 1.62 (s, 1H), 1.96 (s, 2H), 2.14-2.27 (m, 1H), 2.98-3.12 (m, 2H), 3.14-3.28 (m, 2H), 3.44 (s, 1H), 3.49-3.59 (m, 1H), 3.59-3.69 (m, 1H), 7.42 (d, J=8.34Hz, 2H), 7.59-7.64 (m, 2H), 7.64-7.70 (m, 4H).
Step e: preparation intermediate 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4--sulfinic acid sodium salt
In the 20mL scintillation vial, pack into (R)-4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-SULPHURYL CHLORIDE (1.00g, 2.50mmol), S-WAT (0.598g, 4.75mmol) and sodium bicarbonate (0.629g, 7.49mmol).Then add entry (9mL) and the gained mixture is descended stirring 3 hours at 80 ℃.Reactant is filtered and water (3mL) and hexane (10mL) washing.Creamy white solid drying under vacuum is obtained title compound (0.660g, 40%) whole night.
Step F: preparation 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-methyl acetate
In the 20mL scintillation vial, add (R)-4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4--sulfinic acid sodium salt (125mg, 356 μ mol), DMSO (0.5mL) and 2-methyl bromoacetate (43.9 μ l, 462 μ mol).This mixture was stirred 7 days down at 25 ℃.To wherein adding entry (20mL) and DCM (20mL).The gained mixture is filtered, separate each layer and with DCM (20mL) aqueous layer extracted.Will be through merging organic layer water (5mL) washing, through Na
2SO
4Drying is filtered and is concentrated.With this material from DCM/Et
2Recrystallize among the O filters and drying under vacuum.With this substance dissolves in DCM (2mL) and add Et
21M HCl among the O (1.0mL).With this material filtration and dry under vacuum, obtain being the title compound (0.082g, 50% productive rate) of light yellow solid shape.C
22H
27NO
4The accurate mass calculated value of S: 401.2, experimental value: LCMS m/z=402.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 1H), 1.49 (d, J=6.32Hz, 2H), 1.71-1.82 (m, 1H), 2.01-2.25 (m, 2H), 2.30-2.42 (m, 1H), 3.06-3.24 (m, 2H), 3.24-3.37 (m, 2H), 3.53-3.60 (m, 1H), 3.61-3.72 (m, 4H), 3.73-3.81 (m, 1H), 4.40 (s, 2H), 7.49 (d, J=8.34Hz, 2H), 7.72 (d, J=8.34Hz, 2H), 7.88 (d, J=8.34Hz, 2H), 8.00 (d, J=8.59Hz, 2H).
Example 1.3: preparation 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-tert.-butyl acetate (compound 18)
In the 20mL scintillation vial, add (R)-4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4--sulfinic acid sodium salt (200mg, 569 μ mol), DMSO (2.0mL) and 2-bromo-acetic acid tert-butyl (109 μ l, 740 μ mol).This mixture was stirred 3 days down at 25 ℃.To wherein adding entry (20mL) and methylene dichloride (20mL).The gained mixture is filtered, separate each layer and with DCM (20mL) aqueous layer extracted.Will be through merging organic layer water (5mL) washing, through Na
2SO
4Drying is filtered and is concentrated.By preparation HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying crude mixture.(5 * 20mL) extract with saturated potassium carbonate (10mL) neutralization and with DCM with elution part.With organism through Na
2SO
4Drying is filtered also and is concentrated, the title compound (326mg, 40% productive rate) of the waxy solid shape that obtains being white in color.C
25H
33NO
4The accurate mass calculated value of S: 443.6, experimental value: LCMS m/z=444.6 (M+H
+).
Example 1.4: preparation 6-{4-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-1,1-dioxo-1 λ
6-sulfo-chroman-4-ketone (compound 7)
(R)-4-[2-in containing THF (4mL) (2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (adding 6-chloro-1 among the 0.182g, 5mL Smith bottle (Smith vial) 0.78mmol), 1-dioxo-1 λ
6-sulfo-chroman-4-ketone (0.150g, 0.650mmol), potassium acetate (0.414g, 1.95mmol), 2-dicyclohexyl phosphino--2 ', 4 ', 6 '-triisopropyl-biphenyl (X-Phos) (0.016g, 0.033mmol) and acid chloride (II) (0.0029g, 0.013mmol).Use Smith's synthesizer (Smith Synthesizer) (microwave) that this mixture heating up to 120 ℃ is reached 45 minutes.By the diatomite filtration reactant, use EtOAc (10mL) flushing simultaneously.Thick material concentrated and by preparation HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.With the freeze-drying of elution part, obtain being buttery title compound (0.189g, 61% productive rate).C
22H
25NO
3The accurate mass calculated value of S: 383.2, experimental value: LCMS m/z=384.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 1H), 1.49 (d, J=6.57Hz, 2H), and 1.70-1.83 (m, 1H), 2.01-2.23 (m, 2H), and 2.29-2.41 (m, 1H), 3.05-3.23 (m, 2H), and 3.23-3.30 (m, 1H), 3.30-3.33 (m, 2H), 3.37 (t, J=3.37Hz, 2H), 3.48-3.59 (m, 1H), 3.61-3.69 (m, 1H), 3.73-3.83 (m, 1H), 3.86 (t, J=6.01Hz, 2H), 7.47 (d, J=8.34Hz, 2H), 7.67 (d, J=8.34Hz, 2H), 7.99 (d, J=8.18Hz, 1H), 8.08 (dd, J
1=8.17Hz, J
2=1.93Hz, 1H), 8.25 (d, J=2.02Hz, 1H).
Example 1.5: preparation (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 3)
Steps A: preparation intermediate (4-bromophenyl) (2-methoxy ethyl) sulfane
To the 4-bromo thiophenol (2.50g, 12.6mmol) add in the solution in DMF (15mL) sodium hydride (60% dispersion liquid in mineral oil) (0.754g, 18.8mmol), then add 1-bromo-2-methyl ethyl ether (2.62g, 18.8mmol).The gained mixture was at room temperature stirred 18 hours.The reactant dilute with water is also used the EtOAc extracting twice.By flash chromatography on silica gel (0-5%EtOAc in hexane) purifying, obtain being transparent buttery title compound (2.58g, 83% productive rate).
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 3.11 (t, J=6.44Hz, 2H), 3.28-3.31 (m, 3H), 3.56 (t, J=6.44Hz, 2H), 7.28 (d, J=8.59Hz, 2H), 7.43 (d, J=8.59Hz, 2H).
Step B: preparation intermediate 1-bromo-4-(2-methoxy ethyl alkylsulfonyl) benzene
To (4-bromophenyl) (2-methoxy ethyl) sulfane (2.58g, 10.4mmol) add in the solution in DCM (25mL) 3-chloroperoxybenzoic acid (maximum 77%) (4.91g, 21.9mmol).The gained mixture was at room temperature stirred 4 hours.Reactant is extracted three times with 1N NaOH alkalization and with EtOAc.With organism through MgSO
4Drying is filtered and is concentrated, and obtains being transparent buttery title compound (2.91g, 100% productive rate).
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 3.17 (s, 3H), 3.49 (t, J=5.81Hz, 2H), 3.71 (t, J=5.81Hz, 2H), 7.73-7.87 (m, 4H).
Step C: preparation (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine
In the heavy wall bottle, add 1-bromo-4-(the 2-methoxy ethyl alkylsulfonyl) benzene (320mg in the mixture of EtOH (0.75mL) and benzene (2.25mL); 1.15mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (267mg, 1.15mmol), Na
2CO
3The aqueous solution (2M solution, 1.15mL, 2.29mmol) and tetrakis triphenylphosphine palladium (0) (33.1mg, 0.029mmol).The gained reaction mixture was heated 60 minutes down at 100 ℃ under microwave irradiation.Dilute with water reaction mixture and separation of organic substances.Use the EtOAc aqueous layer extracted.To concentrate through merging organism, be dissolved among the DMSO, and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.To extract three times with 1N NaOH alkalization and with EtOAc through merging elution part.Will be through merging organism through MgSO
4Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (2mL).Then add HCl (1M Et
2O solution 0.72mL), adds EtOAc (5mL) then.The gained mixture is concentrated the hydrochloride (303mg, 62% productive rate) of the title compound of the solid state that obtains being white in color.C
22H
29NO
3The accurate mass calculated value of S: 387.2, experimental value: LCMS m/z=388.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.50 (d, J=6.32Hz, 2.7H), 1.70-1.86 (m, 1H), 2.00-2.25 (m, 2H), 2.28-2.43 (m, 1H), 3.04-3.29 (m, 7H), 3.49-3.58 (m, 3H), 3.58-3.70 (m, 1H), and 3.70-3.84 (m, 3H), 7.48 (d, J=7.83Hz, 2H), 7.70 (d, J=7.07Hz, 2H), 7.86 (d, J=7.83Hz, 2H), 7.97 (d, J=7.83Hz, 2H).
Example 1.6: preparation (R)-2-methyl isophthalic acid-2-[4 '-(propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 5)
Use 1-bromo-4-(sulfonyl propyl base) benzene (274mg; 1.04mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (243mg; 1.04mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 52% white solid.C
22H
29NO
2The accurate mass calculated value of S: 371.2, experimental value: LCMS m/z=372.3 (M+H
+);
1HNMR (400MHz, methyl alcohol-d
4) δ ppm 1.01 (t, J=7.45Hz, 3H), 1.33 (d, J=6.82Hz, 0.3H), 1.49 (d, J=6.57Hz, 2.7H), 1.65-1.82 (m, 3H), 2.02-2.22 (m, 2H), and 2.28-2.41 (m, 1H), 3.03-3.30 (m, 6H), 3.49-3.58 (m, 1H), 3.59-3.71 (m, 1H), 3.71-3.83 (m, 1H), and 7.38-7.54 (m, 2H), 7.72 (d, J=8.08Hz, 2H), and 7.81-7.93 (m, 2H), 7.93-8.05 (m, 2H).
Example 1.7: preparation (R)-2-methyl isophthalic acid-[2-(4 '-phenylmethane alkylsulfonyl-biphenyl-4-yl)-ethyl]-tetramethyleneimine (compound 6)
Use 1-(benzyl alkylsulfonyl)-4-bromobenzene (115mg; 0.370mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (86.1mg; 0.370mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 50% yellow solid.C
26H
29NO
2The accurate mass calculated value of S: 419.2, experimental value: LCMS m/z=420.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=7.07Hz, 0.3H), 1.48 (d, J=6.32Hz, 2.7H), 1.68-1.82 (m, 1H), 2.00-2.25 (m, 2H), 2.28-2.41 (m, 1H), and 3.04-3.28 (m, 4H), 3.46-3.59 (m, 1H), 3.58-3.69 (m, 1H), 3.70-3.82 (m, 1H), 4.53 (s, 2H), and 7.07-7.20 (m, 2H), 7.21-7.37 (m, 3H), 7.46 (d, J=8.08Hz, 2H), 7.59-7.82 (m, 6H).
Example 1.8: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 8)
Use 1-bromo-4-(3-methoxy-propyl alkylsulfonyl) benzene (81.0mg; 0.276mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (64.4mg; 0.276mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 53% transparent solid.C
23H
31NO
3The accurate mass calculated value of S: 401.2, experimental value: LCMS m/z=402.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.45 (d, J=6.32Hz, 3H), 1.67-1.83 (m, 1H), 1.83-1.98 (m, 2H), 2.01-2.18 (m, 2H), 2.23-2.40 (m, 1H), and 2.99-3.29 (m, 9H), 3.38-3.53 (m, 3H), 3.53-3.63 (m, 1H), 3.64-3.76 (m, 1H), 7.47 (d, J=8.34Hz, 2H), 7.71 (d, J=8.08Hz, 2H), 7.89 (d, J=8.34Hz, 2H), 7.94-8.02 (m, 2H).
Example 1.9: preparation (R)-2-methyl isophthalic acid-2-[4 '-(2-methyl-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 9)
Use 1-bromo-4-(isobutyl-alkylsulfonyl) benzene (189mg; 0.682mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (159mg; 0.682mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 41% yellow oil.C
23H
31NO
2The accurate mass calculated value of S: 385.2, experimental value: LCMS m/z=386.1 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm1.06 (d, J=6.82Hz, 6H), 1.48 (d, J=6.57Hz, 3H), and 1.70-1.86 (m, 1H), 2.03-2.23 (m, 3H), 2.27-2.41 (m, 1H), 3.07-3.28 (m, 6H), 3.52-3.68 (m, 2H), and 3.67-3.81 (m, 1H), 7.47 (d, J=8.08Hz, 2H), 7.70 (d, J=8.08Hz, 2H), 7.87 (d, J=8.34Hz, 2H), 7.93-8.03 (m, 2H).
Example 1.10: preparation 2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethanol (compound 10)
Use 2-(4-bromophenyl alkylsulfonyl) ethanol (238mg; 0.898mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (209mg; 0.898mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 34% white solid.C
21H
27NO
3The accurate mass calculated value of S: 373.2, experimental value: LCMS m/z=374.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, 0.3H), 1.49 (d, J=6.32Hz, 2.7H), 1.70-1.85 (m, 1H), 2.02-2.20 (m, 2H), 2.28-2.43 (m, 1H), 3.05-3.28 (m, 4H), 3.45 (t, J=6.19Hz, 2H), 3.50-3.59 (m, 1H), 3.59-3.68 (m, 1H), 3.73-3.82 (m, 1H), 3.89 (t, J=6.19Hz, 2H), 7.47 (d, J=8.08Hz, 2H), 7.70 (d, J=8.08Hz, 2H), 7.87 (d, J=8.34Hz, 2H), 7.99 (d, J=8.34Hz, 2H).
Example 1.11: preparation 4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl acetate (compound 11)
Use 2-(4-bromophenyl alkylsulfonyl) ethyl acetate (207mg; 0.674mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (157mg; 0.674mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 6% transparent solid.C
23H
29NO
4The accurate mass calculated value of S: 415.2, experimental value: LCMS m/z=416.7 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm1.15 (m, 3H), 1.33 (d, J=6.82Hz, 0.3H), 1.50 (d, J=6.57Hz, 2.7H), 1.70-1.84 (m, 1H), 2.00-2.23 (m, 2H), 2.29-2.43 (m, 1H), 3.05-3.28 (m, 4H), 3.50-3.59 (m, 1H), 3.59-3.70 (m, 1H), 3.71-3.82 (m, 1H), 4.11 (q, J=7.07Hz, 2H), 4.38 (s, 2H), 7.48 (d, J=8.34Hz, 2H), 7.71 (d, J=8.34Hz, 2H), 7.88 (d, J=8.59Hz, 2H), 8.00 (d, J=8.59Hz, 2H).
Example 1.12: preparation (R)-1-[2-(4 '-pentamethylene alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine (compound 14)
Use 1-bromo-4-(cyclopentyl alkylsulfonyl) benzene (250mg; 0.864mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (202mg; 0.864mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 40% white solid.C
24H
31NO
2The accurate mass calculated value of S: 397.2, experimental value: LCMS m/z=398.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.48 (d, J=6.57Hz, 3H), 1.59-1.80 (m, 5H), 1.84-1.96 (m, 2H), 1.96-2.20 (m, 4H), 2.27-2.42 (m, 1H), and 2.99-3.29 (m, 3H), 3.42-3.59 (m, 2H), 3.59-3.81 (m, 3H), 7.48 (d, J=8.08Hz, 2H), 7.73 (d, J=8.34Hz, 2H), 7.84-7.92 (m, 2H), 7.93-8.04 (m, 2H).
Example 1.13: preparation (R)-1-[2-(4 '-methane sulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine (compound 1)
In the heavy wall bottle, add (R)-1-[2-(4-bromo-the phenyl)-ethyl in the mixture of EtOH (0.75mL) and benzene (2.25mL)]-2-methyl-tetramethyleneimine (200mg; 0.746mmol), 4-(methyl sulphonyl) phenyl-boron dihydroxide (194mg, 0.969mmol), Na
2CO
3The aqueous solution (0.746mL, 1.49mmol, 2M solution) and tetrakis triphenylphosphine palladium (0) (21.5mg, 0.019mmol).The gained reaction mixture was heated 30 minutes down at 100 ℃ under microwave condition.Dilute with water reaction mixture and separation organic phase.Use the EtOAc aqueous layer extracted.To concentrate through merging organism, be dissolved among the DMSO and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.To extract three times with 1N NaOH alkalization and with EtOAc through merging elution part.Will be through merging organism through MgSO
4Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (2mL).Then add HCl (1M Et
2O solution 0.72mL), adds EtOAc (5mL) then.The gained mixture is concentrated the hydrochloride (70.0mg, 25% productive rate) of the title compound of the solid state that obtains being white in color.C
20H
25NO
2The accurate mass calculated value of S: 343.2, experimental value: LCMS m/z=344.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H), 1.70-1.82 (m, 1H), 2.02-2.20 (m, 2H), 2.30-2.40 (m, 1H), 3.06-3.22 (m, 4H), 3.23-3.33 (m, 3H), 3.46-3.57 (m, 1H), 3.59-3.69 (m, 1H), 3.71-3.84 (m, 1H), 7.48 (d, 7=8.34Hz, 2H), 7.70 (d, J=8.34Hz, 2H), 7.87 (d, J=8.59Hz, 2H), 8.01 (d, J=8.59Hz, 2H).
Example 1.14: preparation (R)-2-methyl isophthalic acid-2-[4 '-(propane-2-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 4)
Use (R)-1-[2-(4-bromo-phenyl)-ethyl]-2-methyl-tetramethyleneimine (200mg; 0.746mmol) and 4-(sec.-propyl alkylsulfonyl) phenyl-boron dihydroxide (170mg; 0.746mmol) as initial substance; with with described in the example 1.13 similarly mode prepare title compound, obtain productive rate and be 58% transparent solid.C
22H
29NO
2The accurate mass calculated value of S: 371.2, experimental value: LCMS m/z=372.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.20-1.33 (m, 6H), 1.48 (d, J=6.06Hz, 3H), 1.70-1.87 (m, 1H), 2.04-2.22 (m, 2H), 2.30-2.42 (m, 1H), 3.01-3.29 (m, 3H), 3.32-3.46 (m, 2H), 3.48-3.82 (m, 3H), 7.48 (d, J=7.83Hz, 2H), 7.70 (d, J=7.83Hz, 2H), 7.80-8.05 (m, 4H).
Example 1.15: preparation (R)-1-[2-(4 '-ethane alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine (compound 2)
Use 1-bromo-4-(ethylsulfonyl) benzene (365mg; 1.465mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (342mg; 1.465mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 48% transparent solid.C
21H
27NO
2The accurate mass calculated value of S: 357.2, experimental value: LCMS m/z=358.1 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.27 (t, J=7.33Hz, 3H), 1.35 (d, J=7.07Hz, 0.3H), 1.50 (d, J=6.57Hz, 2.7H), 1.72-1.83 (m, 1H), 2.03-2.23 (m, 2H), and 2.33-2.43 (m, 1H), 3.07-3.23 (m, 2H), 3.23-3.32 (m, 4H), and 3.51-3.61 (m, 1H), 3.63-3.72 (m, 1H), 3.75-3.83 (m, 1H), 7.49 (d, J=8.34Hz, 2H), 7.73 (d, J=8.34Hz, 2H), and 7.88-7.92 (m, 2H), 7.97-8.01 (m, 2H).
Example 1.16: preparation (R)-1-{2-[4 '-(2-oxyethyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 12)
Use 1-bromo-4-(2-ethoxyethyl group alkylsulfonyl) benzene (210mg; 0.716mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (167mg; 0.716mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 13% transparent solid.C
23H
31NO
3The accurate mass calculated value of S: 401.2, experimental value: LCMS m/z=402.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 0.95 (t, J=7.07,3H), 1.33 (d, J=6.57,0.3H), 1.49 (d, J=6.57,2.7H), 1.71-1.82 (m, 1H), 2.03-2.20 (m, 2H), and 2.31-2.40 (m, 1H), 3.07-3.23 (m, 2H), and 3.24-3.29 (m, 1H), 3.32-3.37 (m, 3H), and 3.49-3.60 (m, 3H), 3.60-3.70 (m, 1H), and 3.73-3.82 (m, 3H), 7.48 (d, J=8.34Hz, 2H), 7.70 (d, J=8.34Hz, 2H), 7.85 (d, J=8.59Hz, 2H), 7.98 (m, 2H).
Example 1.17: preparation (R)-1-{2-[3 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 16)
Steps A: preparation intermediate (3-bromophenyl) (2-methoxy ethyl) sulfane
To sodium hydride (96.6mg, 2.42mmol) add in the suspension in DMF (4.2mL) the 3-bromo thiophenol (0.22mL, 2.132mmol).After at room temperature stirring 30 minutes, (0.22mL 2.341mmol) adds in the reaction mixture with 1-bromo-2-methyl ethyl ether.Stir after 17 hours, with reaction mixture H
2O stopped reaction and extract with EtOAc.Will be through merging organic layer H
2O, salt water washing are through MgSO
4Dry and concentrated.By silicagel column purifying resistates, obtain being the title compound (425.1mg, 81%) of colorless oil with the 15%EtOAc/85% hexane.
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 3.13 (t, J=6.5Hz, 2H), 3.33 (s, 3H), 3.57 (t, J=6.5Hz, 2H), 7.20 (dd, J=7.9,7.9Hz, 1H), 7.30-7.35 (m, 2H), 7.50-7.52 (m, 1H).
Step B: preparation intermediate 1-bromo-3-(2-methoxy ethyl alkylsulfonyl) benzene
To (3-bromophenyl) (2-methoxy ethyl) sulfane (425.1mg, 1.72mmol) add in the solution in DCM (8.5mL) 3-chloroperoxybenzoic acid (maximum 77%) (1.09g, 4.88mmol).The gained reaction mixture was at room temperature stirred 21 hours.After finishing, with the saturated NaHCO of reaction mixture
3Stopped reaction also extracts with EtOAc.Will be through merging organic layer H
2O, salt water washing are through MgSO
4Dry and concentrated.By silicagel column purifying resistates, obtain being the product (0.426g, 89%) of colorless oil with the 30%EtOAc/70% hexane.
1HNMR (400MHz, methyl alcohol-d
4) δ ppm 3.172 (s, 3H), 3.514 (t, J=5.7Hz, 2H), 3.719 (t, J=5.7Hz, 2H), 7.540 (dd, J=8.0,8.0Hz, 1H), 7.85-7.91 (m, 2H), 8.06 (dd, J=1.8,1.8Hz, 1H).
Step C: preparation (R)-1-{2-[3 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine
The ethanol of in reaction flask, packing into (0.50mL; 8.563mmo1) with the mixture of benzene (1.5mL) in 1-bromo-3-(2-methoxy ethyl alkylsulfonyl) benzene (200.7mg; 0.719mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (170.1mg; 0.7297mmol), yellow soda ash (0.716mL; 1.432mmol) and tetrakis triphenylphosphine palladium (0) (20.0mg, 0.01731mmol).Use microwave that the gained reaction mixture was heated 1.5 hours down at 100 ℃.After finishing, inhale and shift out organic layer and use the EtOAc aqueous layer extracted.Will be through merging organic layer through MgSO
4Dry and concentrated.By the preparation HPLC purifying, freeze-drying is also handled with HCl, obtains the hydrochloride (152.3mg) of title compound with resistates.C
22H
29NO
3The accurate mass calculated value of S: 387.2, experimental value: LCMS m/z=388.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.48 (d, J=6.5Hz, 3H), 1.71-1.82 (m, 1H), 2.01-2.22 (m, 2H), 2.31-2.41 (m, 1H), 3.06-3.23 (m, 5H), 3.24-3.36 (m, 2H), 3.51-3.58 (m, 3H), and 3.61-3.70 (m, 1H), 3.72-3.80 (m, 3H), 7.48 (d, J=8.3Hz, 2H), 7.68-7.73 (m, 3H), 7.91 (ddd, J=1.1,1.6,7.9Hz, 1H), 7.97 (ddd, J=1.1,1.7,7.8Hz, 1H), 8.13 (dd, J=1.7,1.7Hz, 1H).
Example 1.18: preparation (R)-1-[2-(4 '-ethene alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine (compound 13)
The ethanol of in reaction flask, packing into (0.500mL; 8.56mmol) with the mixture of benzene (1.5mL) in isopropylformic acid 2-(4-bromophenyl alkylsulfonyl) ethyl ester (120mg; 0.357mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (85.7mg; 0.368mmol), yellow soda ash (0.357mL; 0.714mmol) and tetrakis triphenylphosphine palladium (0) (11.6mg, 10.0 μ mol).Use microwave irradiation that the gained reaction mixture was heated 1.5 hours down at 100 ℃.After finishing, inhale and shift out organic layer and use the EtOAc aqueous layer extracted.Will be through merging organic layer through MgSO
4Dry and concentrated.Will be through merging organic layer through MgSO
4Dry and concentrated.By the preparation HPLC purifying, freeze-drying is also handled with HCl, obtains the hydrochloride (16.7mg) of title compound with resistates.C
21H
25NO
2The accurate mass calculated value of S: 355.2, experimental value: LCMS m/z=356.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.49 (d, J=6.5Hz, 3H), 1.71-1.82 (m, 1H), 2.02-2.21 (m, 2H), 2.30-2.40 (m, 1H), 3.07-3.23 (m, 2H), 3.24-3.35 (m, 2H), 3.49-3.60 (m, 1H), 3.60-3.70 (m, 1H), 3.73-3.81 (m, 1H), 6.14 (dd, J=0.0,9.9Hz, 1H), 6.43 (dd, J=0.0,16.5Hz, 1H), 6.93 (dd, J=9.9,16.5Hz, 1H), 7.48 (d, J=8.3Hz, 2H), 7.70 (d, J=8.2Hz, 2H), 7.84-7.88 (m, 2H), 7.93-7.97 (m, 2H).
Example 1.19: preparation 2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-3-alkylsulfonyl }-ethanol (compound 17)
Use 2-(3-bromophenyl alkylsulfonyl) ethanol (116.5mg; 0.439mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (102.8mg; 0.4410mmol) as initial substance; with with described in the example 1.17 step C similarly mode prepare title compound, obtain productive rate and be 51% white solid.C
21H
27NO
3The accurate mass calculated value of S: 373.2, experimental value: LCMS m/z=374.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm1.487 (d, J=6.5Hz, 3H), 1.71-1.82 (m, 1H), and 2.01-2.27 (m, 2H), 2.31-2.41 (m, 1H), and 3.06-3.22 (m, 2H), 3.24-3.35 (m, 2H), 3.474 (t, J=6.1Hz, 2H), 3.49-3.60 (m, 1H), 3.61-3.70 (m, 1H), 3.72-3.80 (m, 1H), 3.90 (t, J=6.1Hz, 2H), 7.48 (d, J=8.3Hz, 2H), 7.68-7.74 (m, 3H), 7.90-7.94 (m, 1H), 7.96-8.00 (m, 1H), 8.15 (dd, J=1.7,1.7Hz, 1H).
Example 1.20: preparation 3-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-third-1-alcohol (compound 15)
Use 3-(4-bromophenyl alkylsulfonyl) third-1-alcohol (200mg; 0.716mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (167mg; 0.716mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 13% transparent solid.C
22H
29NO
3The accurate mass calculated value of S: 387.2, experimental value: LCMS m/z=388.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.49 (d, J=6.32Hz, 2.7H), 1.71-1.82 (m, 1H), 1.84-1.93 (m, 2H), 2.01-2.21 (m, 2H), 2.31-2.41 (m, 1H), 3.06-3.23 (m, 2H), 3.24-3.29 (m, 2H), 3.32-3.36 (m, 2H), 3.49-3.70 (m, 4H), 3.73-3.80 (m, 1H), 7.48 (d, J=8.08Hz, 2H), 7.72 (d, J=8.34Hz, 2H), 7.89 (d, 7=8.34Hz, 2H), 7.97-8.01 (m, 2H).
Example 1.21: preparation intermediate 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium
Steps A: preparation 2-biphenyl-4-base-ethanol
Be the hydrogen by product that dilution is emitted continuously from reactor, in whole process of preparation, keep nitrogen and flow, use the aqueous sodium hydroxide solution stopped reaction up to finishing by the powerful of reactor.In the 50L reactor that contains isopropyl acetate (16.7L), add sodium borohydride (0.762Kg, 20.14 moles, 1.60 equivalents).(1L) is flushed to sodium borohydride in the reactor with extra isopropyl acetate.Then enough add biphenylacetic acid (2.67Kg, 12.58 moles, 1.00 equivalents) lentamente under the reactor jacket cooling, will maintain under 0 ℃-8 ℃ through the stirred reactor inclusion.(1L) is flushed to felbinac in the reactor with extra isopropyl acetate.Then reactor content being warmed up to 25 ℃ reaches one hour and then is cooled to-5 ℃-0 ℃ again.Then add boron trifluoride ethyl ether complex (3.584Kg, 25.25 moles, 2.01 equivalents) with constant rate of speed, under the reactor jacket cooling, will maintain 0 ℃-5 ℃ simultaneously through the stirred reactor inclusion through three hours period.Reactor content is warmed up to 20 ℃-25 ℃, and under described temperature, continues to stir, up to confirming that according to liquid chromatography biphenylacetic acid transforms (realizing usually transforming fully substantially) substantially fully in 1-12 hour.Then enough add the solution of sodium hydroxide (3.355Kg, 83.9 moles, 6.67 equivalents) in water (15.0L) lentamente under the reactor jacket cooling, will maintain 10 ℃-20 ℃ through the stirred reactor inclusion.Reactor content is heated to 40 ℃, and under described temperature, continue stirred one hour or all dissolve up to all solids substantially.Then will be cooled to 15 ℃-20 ℃ through stirring the mixture, and make respectively and be separated.Discharge water, and water (4 * 5.0L) washing organic (upper strata) phases.By vacuum distilling upper organic phase is concentrated to the 8L volume being elevated under the temperature that is no more than 60 ℃.Reactor content is cooled to 20 ℃, and adds heptane (20L).To be concentrated to the 16L volume through the stirred reactor inclusion by vacuum distilling being elevated under the temperature that is no more than 40 ℃.To be cooled to 20 ℃ through the stirred reactor inclusion, under described temperature, stir at least 2 hours, and subsequent filtration.Solid obtains title compound 2-biphenyl-4-base-ethanol with heptane (5L) washing and 25 ℃ of following vacuum-dryings after filtration.Output is about 2.148Kg (10.83 moles, 86.1%).
Step B: preparation 4 '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid
Wash in the 30L reactor that contains 1-chlorobutane (11.4L) in the device and add 2-biphenyl-4-base-ethanol (1.9323Kg under nitrogen, stirring and lead to aqueous sodium hydroxide washes, 9.75 mole, 1.00 equivalent) and N, N-N,N-DIMETHYLACETAMIDE (DMA, 84.3g, 0.968 mole, 0.099 equivalent).Then enough add thionyl chloride (1.468Kg, 12.34 moles, 1.27 equivalents) lentamente under the reactor jacket cooling, will maintain 12 ℃-20 ℃ through the stirred reactor inclusion.(50mL) is flushed to thionyl chloride in the reactor with extra 1-chlorobutane.Reactor content is heated to 55 ℃, and under described temperature, continues to stir 11 hours, up to finishing substantially and be converted into 4-(2-chloro-ethyl)-biphenyl according to liquid chromatography confirmation 2-biphenyl-4-base-ethanol.Add more 1-chlorobutanes (3.9L), and reactor content is cooled to-5 ℃.Then enough add chlorsulfonic acid (1.648Kg, 14.14 moles, 1.45 equivalents) lentamente under the reactor jacket cooling, will maintain-5 ℃ to 1 ℃ through the stirred reactor inclusion.(50mL) is flushed to chlorsulfonic acid in the reactor with extra 1-chlorobutane.Reactor content is warmed up to 20 ℃-23 ℃, and under described temperature, continue stirred 17 hours, up to confirm according to liquid chromatography 4-(2-chloro-ethyl)-biphenyl finish substantially be converted into 4 '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid.Reaction mixture is filtered, and solid arrives constant weight with 1-chlorobutane (11.5L) washing and 55 ℃ of following vacuum-dryings after filtration, obtain 4 '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid (2.674Kg, 9.01 mole, 92.4% productive rate), if itself and air are kept in touch, it will absorb big water gaging so.
Step C: preparation 4 '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE
Wash and contain thionyl chloride (3.82Kg in the device under nitrogen, stirring and lead to aqueous sodium hydroxide washes, 32.1 mole, 11.5 enough add 4 in reactor equivalent) lentamente '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid (0.831Kg (after) about 12.5 weight % water-content corrections, 2.80 mole, 1.00 equivalents) under the reactor jacket cooling, will maintain 5 ℃-20 ℃ through the stirred reactor inclusion.Then enough add N,N-dimethylacetamide (28.1g, 0.323 mole, 0.115 equivalent) lentamente under the reactor jacket cooling, will maintain-1 ℃ to 5 ℃ through the stirred reactor inclusion.Reactor content is heated to 65 ℃, and under described temperature, continue stirred 6.5 hours, up to confirm 4 according to liquid chromatography '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid is converted into 4 substantially fully '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE.After reactor content has been cooled to 23 ℃, adds heptane (4.75L), and continue to stir 1.5 hours down at 23 ℃.Follow filter reaction mixture.Will be after filtration solid use heptane (being followed successively by 1L and 3L) and water (5.4L) washing successively and arrive constant weight 40 ℃ of following vacuum-dryings, obtain 4 '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE (0.6955Kg, 2.21 moles, 78.8% productive rate).
Step D: preparation 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium
With S-WAT (600.3g, 4.76 moles, 5.00 equivalents), Na
2HPO
4The mixture of (135.0g, 0.951mol, 1.00 equivalents), benzyltriethylammonium chloride (11.71g, 47.6mmol, 0.0500 equivalent) and water (2500mL) stirs and be heated to 37 ℃ under nitrogen.In gained solution, add 4 '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE (300.2g, 0.952 mole, 1.00 equivalents), under nitrogen, keep stirring simultaneously.The temperature of brown reaction paste is 48 ℃ and then is elevated to 60 ℃ when reinforced the end.After under the described temperature reaction mixture being stirred 13.5 hours, LC/MS analyzes and discloses initial substance and transform fully, and makes the cool to room temperature that stirs the mixture.Product mixtures was stirred two hours down and then filters at 24 ℃-29 ℃.To solid water (600mL after filtration, then 400mL) and acetonitrile (2 * 600mL) washings also then under vacuum 60 ℃ of dryings down, obtain containing sulfonic acid (8.8LC/MS area %) as impurity and S-WAT white thick 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium (243.8g, 0.805 mole, 84.6% productive rate).
Unless remove S-WAT impurity, otherwise 4 '-subsequent alkylation of (2-chloroethyl)-4-biphenyl-sulfinic acid sodium can not proceed to fully and transform.Therefore, remove S-WAT impurity by following steps: under nitrogen 40 ℃ down will be thick 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium (231.17g) in water (2.0L), stirred 15 minutes and follow reclaim by vacuum filtration pure 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium, water (2 * 1.0L) and acetonitrile (2 * 500mL) washings are and 60 ℃ of following vacuum-dryings.
Example 1.22: preparation (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-pyrrolidine hydrochloride (compound 3 is hydrochloride form)
Steps A: preparation 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl
Under nitrogen to Na through stirring
2HPO
4(468.9mg, 3.303mmol, 1.00 bromination tetra-n-butyl ammonium (106.5mg equivalent),, 0.3303mmol, 0.100 equivalent), 4 '-add 2-methoxy ethyl bromide (0.326mL in the mixture of (2-chloroethyl)-4-biphenyl-sulfinic acid sodium (1.00g, 3.303mmol, 1.00 equivalents) and water (5.0mL), 3.468 mmole, 1.05 equivalents).The gained mixture was stirred 3.5 hours in 80 ℃ of oil baths, up to confirm 4 according to LC/MS '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium finishes substantially and is converted into 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl.Stop heating, and when reactor content is 55 ℃-60 ℃, add methyl alcohol (10.0mL).After at room temperature reaction mixture being stirred 4.5 hours, with its filtration.White solid washes with water and 45 ℃ of following vacuum-dryings, obtains 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl (0.989g, 2.92 mmoles, 88.4% productive rate) after filtration.
Step B: preparation (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-pyrrolidine hydrochloride (compound 3 is hydrochloride form)
Under nitrogen to 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl (98mg through stirring; 0.289 mmole; 1.00 equivalent) and in the mixture of acetonitrile (1.0mL) add salt of wormwood (47.9mg; 0.347 mmole; 1.20 equivalent) and potassiumiodide (48mg; 0.289 mmole, 1.00 equivalents).After at room temperature the gained mixture being stirred 15 minutes, add (R)-(-)-2-crassitude (24.6mg, 0.289 mmole, 1.00 equivalents).60 ℃ down stir 16 hours after, 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl is converted into (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl-transformation efficiency of the free alkali of 2-methyl-tetramethyleneimine is about 50%.Adding more (R)-(-)-2-crassitude (9.8mg; 0.115 mmole; 0.40 equivalent) and at 80 ℃ continue stirring down after 40 hours; analyze according to LC/MS, 4-(2-chloro-ethyl)-4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl is converted into (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl substantially fully]-ethyl }-free alkali of 2-methyl-tetramethyleneimine.The reaction mixture cool to room temperature is also filtered to remove sylvite.With filtrate evaporation and be dissolved in the ethyl acetate.With 5 weight %HCl aqueous solution extraction gained solution.Yellow soda ash is added in the aqueous extract product is converted into its free alkali, be extracted in the ethyl acetate.With HCl gas processing acetic acid ethyl ester extract, obtain being (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl of hydrochloride form]-ethyl }-2-methyl-tetramethyleneimine.
Example 1.23: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 8)
Steps A: preparation 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl
Under nitrogen to Na through stirring
2HPO
4(15.84g, 111.6mmol, 1.00 equivalent), bromination tetra-n-butyl ammonium (3.60g, 11.2mmol, 0.100 equivalent), Potassium Bromide (13.28g, 111.6 mmole, 1.00 equivalent), 4 '-add 2-methoxy-propyl bromide (18.78g in the mixture of (2-chloroethyl)-4-biphenyl-sulfinic acid sodium (33.78g, 111.6mmol, 1.00 equivalents) and water (169mL), 122.7 mmole, 1.10 equivalents).The gained mixture is stirred in 80 ℃ of oil baths, up to confirm 4 according to stratographic analysis '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium is converted into 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl substantially fully.With reaction mixture cooling and use ethyl acetate extraction.Acetic acid ethyl ester extract is filtered to remove the resistates that remaining bromination tetra-n-butyl ammonium also then is evaporated to 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl by the silica gel plunger, and it is leaving standstill after fixing.
Step B: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine
Under nitrogen to 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl (101.9mg through stirring; 0.289 mmole; 1.00 equivalent) and in the mixture of acetonitrile (1.0mL) add salt of wormwood (47.9mg; 0.347 mmole; 1.20 equivalent) and potassiumiodide (48mg; 0.289 mmole, 1.00 equivalents).After at room temperature the gained mixture being stirred 15 minutes, add (R)-(-)-2-crassitude (24.6mg, 0.289 mmole, 1.00 equivalents).After stirring 16 hours under 60 ℃; add more (R)-(-)-2-crassitude (9.8mg; 0.115 mmole; 0.40 equivalent); and continue down to stir at 80 ℃, up to being converted into (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl substantially fully according to stratographic analysis 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl]-ethyl }-2-methyl-tetramethyleneimine.The reaction mixture cool to room temperature is also filtered to remove sylvite.With filtrate evaporation and be dissolved in the ethyl acetate.With 5 weight %HCl aqueous solution extraction gained solution.Yellow soda ash is added in the aqueous extract so that the hydrochloride of title compound is converted into free alkali, be extracted in the ethyl acetate.Evaporation of acetic acid ethyl ester extract obtains (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine.
Example 1.24: preparation (R)-2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-methylmethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 26)
Steps A: preparation intermediate 4-((4-bromophenyl sulfenyl) methyl)-tetrahydrochysene-2H-pyrans
Use 4-(brooethyl)-tetrahydrochysene-2H-pyrans (0.663g, 3.702mmol), to prepare title compound with similar mode described in example 1.5 steps A.By flash chromatography on silica gel (10%EtOAc in hexane) purifying, obtain being transparent buttery title compound (0.467g, 87.8%).
1H NMR(400MHz，CDCl
3)δppm 1.29-1.42(m，2H)，1.68-1.82(m，3H)，2.83(d，J＝6.57Hz，2H)，3.35(t，J＝11.62Hz，2H)，3.97(dd，J＝11.37，3.79Hz，2H)，7.16-7.21(m，2H)，7.38-7.43(m，2H)。
Step B: preparation intermediate 4-((4-bromophenyl alkylsulfonyl) methyl)-tetrahydrochysene-2H-pyrans
To 4-((4-bromophenyl sulfenyl) methyl)-(0.465g 1.619mmol) adds in the entry (3mL) in the solution in THF (2mL) tetrahydrochysene-2H-pyrans
(2.19g, 3.562mmol).The gained mixture was at room temperature stirred 4 hours.The reactant dilute with water is also used the EtOAc extracting twice.With organic phase through MgSO
4Drying is filtered and is concentrated, and obtains being transparent buttery title compound (0.432g, 83.5%).
1H NMR(400MHz，CDCl
3)δppm 1.38-1.51(m，2H)，1.81(dd，J＝13.14，1.77Hz，2H)，2.20-2.33(m，1H)，3.01(d，J＝6.32Hz，2H)，3.37-3.45(m，2H)，3.93(dd，J＝11.37，3.54Hz，2H)，7.71-7.81(m，4H)。
Step C: preparation (R)-2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-methylmethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 26)
Use 4-((4-bromophenyl alkylsulfonyl) methyl)-tetrahydrochysene-2H-pyrans (385mg; 1.206mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (385mg; 1.206mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 60% white solid.C
25H
33NO
3The accurate mass calculated value of S: 427.2, experimental value: LCMS m/z=428.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.37-1.51 (m, 4.7H), 1.71-1.83 (m, 3H), 2.01-2.22 (m, 3H), and 2.30-2.40 (m, 1H), 3.07-3.20 (m, 2H), and 3.20-3.24 (m, 2H), 3.24-3.29 (m, 2H), and 3.35-3.44 (m, 2H), 3.49-3.59 (m, 1H), and 3.61-3.69 (m, 1H), 3.73-3.81 (m, 1H), 3.88 (dd, J=11.62,2.27Hz, 2H), 7.48 (d, J=8.08Hz, 2H), 7.71 (d, J=8.08Hz, 2H), 7.89 (d, J=8.34Hz, 2H), 7.97-8.01 (m, 2H).
Example 1.25: preparation 2-methane sulfonyl-5-{4-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyridine (compound 22)
Use 5-bromo-2-(methyl sulphonyl) pyridine (150mg; 0.635mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (163mg; 0.699mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 16% white solid (hydrochloride).C
19H
24N
2O
2The accurate mass calculated value of S: 344.2, experimental value: LCMS m/z=345.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.44-1.54 (m, 2.7H), 1.80 (s, 1H), 2.12 (d, J=13.89Hz, 2H), 2.35 (s, 1H), 3.08-3.22 (m, 2H), 3.22-3.35 (m, 5H), 3.49-3.71 (m, 2H), 3.72-3.83 (m, 1H), 7.53 (d, J=8.08Hz, 2H), 7.76 (d, J=8.08Hz, 2H), 8.15 (d, J=8.08Hz, 1H), 8.33 (dd, J=8.21,2.15Hz, 1H), 9.00 (d, J=1.77Hz, 1H).
Example 1.26: preparation 5-methane sulfonyl-2-{4-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyridine (compound 33)
Use 2-bromo-5-(methyl sulphonyl) pyridine (150mg; 0.635mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (163mg; 0.699mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 14% yellow oil (hydrochloride).C
19H
24N
2O
2The accurate mass calculated value of S: 344.2, experimental value: LCMS m/z=345.1 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.57Hz, 0.3H), 1.50 (d, J=6.32Hz, 2.7H), 1.70-1.85 (m, 1H), 2.01-2.22 (m, 2H), 2.28-2.42 (m, 1H), 3.11-3.38 (m, 7H), 3.49-3.61 (m, 1H), 3.61-3.72 (m, 1H), 3.72-3.84 (m, 1H), 7.55 (d, J=7.83Hz, 2H), 8.12 (d, J=7.83Hz, 2H), 8.19 (d, J=8.59Hz, 1H), 8.47 (dd, J=8.34,2.02Hz, 1H), 9.14 (d, J=2.02Hz, 1H).
Example 1.27: preparation (R)-1-[2-(3 '-methane sulfonyl-4 '-methyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine (compound 27)
Use 4-bromo-1-methyl-2-(methyl sulphonyl) benzene (200mg; 0.803mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (206mg; 0.883mmol) as initial substance; with with described in the example 1.5 step C similarly mode prepare title compound, obtain productive rate and be 67% yellow oil (hydrochloride).C
21H
27NO
2The accurate mass calculated value of S: 357.2, experimental value: LCMS m/z=358.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.32 (dd, J=6.82,1.77Hz, 0.3H), 1.49 (dd, J=6.44,1.89Hz, 2.7H), and 1.70-1.84 (m, 1H), 1.99-2.23 (m, 2H), 2.33 (d, J=6.82Hz, 1H), 2.69-2.77 (m, 3H), 3.07-3.37 (m, 7H), and 3.48-3.70 (m, 2H), 3.71-3.83 (m, 1H), 7.42-7.55 (m, 3H), 7.64 (d, J=6.32Hz, 2H), 7.84 (d, J=7.83Hz, 1H), 8.19 (s, 1H).
Example 1.28: preparation 3-methane sulfonyl-4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-formic acid (compound 20)
In bottle, add 4-bromo-2-(methyl sulphonyl) phenylformic acid in the mixture of EtOH (1mL) and benzene (3mL) (200mg, 0.717mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (184mg, 0.788mmol), Na
2CO
3The aqueous solution (2M solution, 0.717mL, 1.43mmol) and tetrakis triphenylphosphine palladium (0) (25mg, 0.022mmol).The gained reaction mixture was heated 60 minutes down at 100 ℃ under microwave irradiation.Subsequently, suction is shifted out organic layer and is used the EtOAc aqueous layer extracted.Crude mixture concentrated and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.With the freeze-drying of elution part, obtain productive rate and be the title compound (tfa salt) of 9% the solid state that is white in color.C
21H
25NO
4The accurate mass calculated value of S: 387.2, experimental value: LCMS m/z=388.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.32 (d, J=5.81Hz, 0.3H), 1.48 (d, J=5.81Hz, 2.7H), 1.68-1.82 (m, 1H), 1.99-2.24 (m, 2H), 2.28-2.41 (m, 1H), 3.02-3.35 (m, 4H), 3.42-3.48 (m, 3H), 3.48-3.59 (m, 1H), 3.59-3.71 (m, 1H), 3.71-3.82 (m, 1H), 7.48 (d, J=8.08Hz, 2H), 7.72 (d, J=8.34Hz, 2H), 7.89 (d, J=7.83Hz, 1H), 8.02 (dd, J=7.96,1.89Hz, 1H), 8.31 (d, J=1.77Hz, 1H).
Example 1.29: preparation 2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethamine (compound 31)
Use 2-(4-chloro-phenyl-alkylsulfonyl) ethamine (125mg; 0.569mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (146mg; 0.626mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 25% white solid (tfa salt).C
21H
28N
2O
2The accurate mass calculated value of S: 372.2, experimental value: LCMS m/z=373.1 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm1.26-1.35 (m, 0.3H), 1.42-1.50 (m, 2.7H), 1.67-1.82 (m, 1H), 1.97-2.20 (m, 2H), 2.27-2.40 (m, 1H), 2.95-3.38 (m, 4H), 3.44-3.67 (m, 6H), 3.68-3.82 (m, 1H), 7.24-7.38 (m, 3H), 7.69-7.75 (m, 4H), and 7.95-8.01 (m, 4H).
Example 1.30: preparation 3-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-propionic acid (compound 28)
Use 3-(4-chloro-phenyl-alkylsulfonyl) propionic acid (200mg; 0.804mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (206mg; 0.885mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 6% yellow oil (tfa salt).C
22H
27NO
4The accurate mass calculated value of S: 401.2, experimental value: LCMS m/z=402.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.47 (d, J=6.57Hz, 3H), 1.67-1.81 (m, 1H), 1.98-2.25 (m, 2H), 2.36 (m, 1H), 2.69 (t, J=7.45Hz, 2H), and 3.03-3.37 (m, 4H), 3.53 (t, J=7.33Hz, 3H), and 3.60-3.82 (m, 2H), 7.48 (d, J=8.08Hz, 2H), 7.73 (d, J=8.34Hz, 2H), 7.90 (d, J=8.34Hz, 2H), 8.00 (d, J=8.33Hz, 2H).
Example 1.31: preparation 2-methane sulfonyl-5-{4-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyrimidine (compound 24)
Use 5-chloro-2-(methyl sulphonyl) pyrimidine (100mg; 0.519mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (133mg; 0.571mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 5% yellow oil (tfa salt).C
18H
23N
3O
2The accurate matter 0 amount calculated value of S: 345.2, experimental value: LCMS m/z=346.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.24-1.35 (m, 0.3H), 1.40-1.53 (m, 2.7H), 1.68-1.83 (m, 1H), and 1.98-2.23 (m, 2H), 2.25-2.42 (m, 1H), and 2.93-3.35 (m, 5H), 3.37-3.45 (m, 2H), and 3.45-3.83 (m, 3H), 7.24-7.44 (m, 3H), and 7.51-7.64 (m, 1H), 7.82 (d, J=8.08Hz, 1H), 9.26 (s, 1H).
Example 1.32: the preparation cyclohexyl-(2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-amine (compound 32)
Use N-(2-(4-chloro-phenyl-alkylsulfonyl) ethyl) hexahydroaniline (100mg; 0.331mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (85mg; 0.364mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 71% brown oil (tfa salt).C
27H
38N
2O
2The accurate mass calculated value of S: 454.3, experimental value: LCMS m/z=455.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.14-1.43 (m, 6H), 1.48 (d, J=6.32Hz, 3H), 1.60-1.94 (m, 4H), and 1.99-2.22 (m, 4H), 2.27-2.41 (m, 1H), 3.04-3.35 (m, 5H), and 3.36-3.48 (m, 2H), 3.47-3.58 (m, 1H), 3.58-3.71 (m, 3H), and 3.72-3.84 (m, 1H), 7.49 (d, J=8.08Hz, 2H), 7.73 (d, J=8.34Hz, 2H), 7.94 (d, J=8.34Hz, 2H), 8.02-8.10 (d, J=8.59Hz, 2H).
Example 1.33: preparation 1-(2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-piperidines-4-formonitrile HCN (compound 29)
Use 1-(2-(4-chloro-phenyl-alkylsulfonyl) ethyl) piperidines-4-formonitrile HCN (100mg; 0.320mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (82mg; 0.352mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 73% yellow oil (tfa salt).C
27H
35N
3O
2The accurate mass calculated value of S: 465.2, experimental value: LCMS m/z=466.4 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H), 1.67-1.85 (m, 1H), 1.99-2.42 (m, 7H), 3.02-3.36 (m, 7H), 3.36-3.72 (m, 6H), 3.72-3.91 (m, 3H), 7.48 (d, J=8.08Hz, 2H), 7.72 (d, J=8.08Hz, 2H), 7.93 (d, J=8.34Hz, 2H), 8.05 (d, J=8.34Hz, 2H).
Example 1.34: preparation 4-(2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-morpholine (compound 25)
Use 4-(2-(4-chloro-phenyl-alkylsulfonyl) ethyl) morpholine (100mg; 0.345mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (89mg; 0.380mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 83% yellow oil (tfa salt).C
25H
34N
2O
3The accurate mass calculated value of S: 442.2, experimental value: LCMS m/z=443.3 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.83Hz, 0.3H), 1.47 (d, J=6.57Hz, 2.7H), 1.68-1.84 (m, 1H), 1.98-2.24 (m, 2H), 2.27-2.42 (m, 1H), 3.04-3.45 (m, 7H), 3.45-3.71 (m, 5H), and 3.70-4.08 (m, 7H), 7.48 (d, J=8.34Hz, 2H), 7.72 (d, J=8.34Hz, 2H), 7.93 (d, J=8.84Hz, 2H), 8.05 (d, J=8.58Hz, 2H).
Example 1.35: preparation (R)-2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 21)
Steps A: preparation intermediate 4-(4-bromophenyl sulfenyl)-tetrahydrochysene-2H-pyrans
To the 4-bromo thiophenol (300mg, 1.60mmol) add in the solution in DMF (3mL) sodium hydride (60% dispersion liquid in mineral oil) (95mg, 2.38mmol) and 4-bromo-tetrahydrochysene-2H-pyrans (458mg, 1.75mmol).The gained mixture was at room temperature stirred 18 hours.The reactant dilute with water is also used the EtOAc extracting twice.By flash chromatography on silica gel (0-5%EtOAc in the hexane) purifying, obtain being transparent buttery title compound (340mg, 78%).
1H NMR(400MHz，CDCl
3)δppm 1.60-1.76(m，2H)，1.92(dd，J＝11.87，1.52Hz，2H)，3.20-3.33(m，1H)，3.39-3.51(m，2H)，3.93-4.05(m，2H)，7.28-7.34(m，2H)，7.42-7.49(m，2H)。
Step B: preparation intermediate 4-(4-bromophenyl alkylsulfonyl)-tetrahydrochysene-2H-pyrans
(580mg 2.12mmol) adds in the solution in THF/ water (10mL/5mL) to 4-(4-bromophenyl sulfenyl)-tetrahydrochysene-2H-pyrans
(1.57g, 2.55mmol).The gained mixture was at room temperature stirred 18 hours.The reactant dilute with water is also used the EtOAc extracting twice.Will be through merging organic layer through MgSO
4Drying is filtered also and is concentrated, the title compound (620mg, 96%) of the solid state that obtains being white in color.C
11H
13BrO
3The accurate mass calculated value of S: 304.0, experimental value: LCMS m/z (%)=305.1 (M+H
+ 79Br, 100%), 307.1 (M+H
+ 81Br, 97%);
1H NMR (400MHz, CDCl
3) δ ppm 1.73-1.88 (m, 2H), 1.89-1.98 (m, 2H), 3.10-3.23 (m, 1H), 3.30-3.42 (m, 2H), 4.04-4.16 (m, 2H), 7.77 (s, 4H).
Step C: preparation (R)-2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 21)
In bottle, add 4-(4-bromophenyl alkylsulfonyl)-tetrahydrochysene-2H-pyrans in the mixture of EtOH (1mL) and benzene (3mL) (500mg, 1.64mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (420mg, 1.80mmol), Na
2CO
3The aqueous solution (2M solution, 1.64mL, 3.28mmol) and tetrakis triphenylphosphine palladium (0) (57mg, 0.049mmol).The gained reaction mixture was heated 60 minutes down at 100 ℃ under microwave irradiation.The dilute with water reaction mixture is also removed organic phase.Use the EtOAc aqueous layer extracted.To concentrate through merging organic layer, be dissolved in ACN/H
2Among the O (containing AcOH) and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.Elution part is merged, use 2M Na
2CO
3Alkalization and with EtOAc extraction three times.Will be through merging organic layer through MgSO
4Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (5mL).Then add HCl (1M Et
2O solution 1.65mL), adds EtOAc (5mL) then.The gained mixture is concentrated the hydrochloride (408mg, 55% productive rate) of the title compound of the solid state that obtains being white in color.C
24H
31NO
3The accurate mass calculated value of S: 413.2, experimental value: LCMS m/z=414.3 (M+H
+);
1H NMR (400MHz, CDCl
3) δ ppm 1.22 (d, J=6.57Hz, 0.4H), 1.62 (d, J=5.56Hz, 2.6H), 1.67-2.10 (m, 6H), 2.11-2.31 (m, 2H), 2.82 (s, 2H), 3.04-3.22 (m, 3H), 3.22-3.35 (m, 2H), 3.49 (s, 2H), 3.86-3.96 (m, 1H), 4.00 (dd, J=11.49,3.92Hz, 2H), 7.33 (d, J=7.58Hz, 2H), 7.50 (d, J=7.58Hz, 2H), 7.67 (d, J=8.08Hz, 2H), 7.85 (d, J=8.34Hz, 2H).
Example 1.36: preparation (R)-1-{2-[4 '-(2-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 23)
Adding (R)-2-methyl isophthalic acid in the 4mL bottle-2-[4 '-(third-2-alkene-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine trifluoroacetate (10mg; 21.43 μ mol), methyl alcohol (0.5mL) and sodium methylate (25%; in MeOH) (19.60 μ l, 85.74 μ mol).With reaction soln stir about 20 hours at ambient temperature, add trifluoroacetic acid (8.3 μ L, 107 μ mol) and with the gained solution concentration, obtain being dense sticky property buttery title compound this moment.C
23H
31NO
3The accurate mass calculated value of S: 401.2, experimental value: LCMS m/z=402.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.22 (d, J=6.32Hz, 3H), 1.32 (d, J=6.82Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H), 1.68-1.85 (m, 1H), and 1.98-2.20 (m, 2H), 2.28-2.41 (m, 1H), 3.05-3.15 (m, 2H), 3.17 (s, 3H), 3.19-3.29 (m, 2H), and 3.33-3.37 (m, 1H), 3.49 (d, J=7.58Hz, 1H), 3.53 (d, J=7.58Hz, 1H), 3.58-3.71 (m, 1H), 3.72-3.90 (m, 2H), 7.47 (d, J=8.34Hz, 2H), 7.70 (d, J=8.08Hz, 2H), 7.87 (d, J=8.59Hz, 2H), 7.98 (d, J=8.59Hz, 2H).
Example 1.37: preparation (R)-2-methyl isophthalic acid-2-[4 '-(third-2-alkene-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine (compound 30)
In the 4mL bottle, add (R)-4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4--sulfinic acid sodium salt (200mg, 569 μ mol), DMSO (2.0mL) and allyl bromide 98 (89.5mg, 64.0 μ l, 740 μ mol).Mixture was stirred 6 hours down at 80 ℃, add DCM (20mL) this moment.With the gained suspension filtered, water (10mL) washing is through Na
2SO
4Dry and concentrated.By preparation HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying crude mixture.Elution part is merged and freeze-drying, obtain being dense sticky property buttery title compound (77.6mg, 29%).C
22H
27NO
2The accurate mass calculated value of S: 369.2, experimental value: LCMS m/z=370.1 (M+H
+);
1HNMR (400MHz, CDCl
3) δ ppm 1.28 (d, J=6.82Hz, 0.3H), 1.56 (d, J=6.57Hz, 2.7H), 1.90-2.10 (m, 2H), 2.19-2.32 (m, 2H), 2.85-3.03 (m, 2H), 3.04-3.16 (m, 1H), 3.16-3.36 (m, 2H), and 3.57-3.68 (m, 1H), 3.85 (d, J=7.33Hz, 2H), and 4.00-4.18 (m, 1H), 5.20 (dd, J=16.93,1.01Hz, 1H), 5.37 (d, J=10.11Hz, 1H), 5.76-5.90 (m, 1H), 7.37 (d, J=8.08Hz, 2H), 7.57 (d, J=8.08Hz, 2H), 7.72 (d, J=8.59Hz, 2H), 7.92 (d .J=8.59Hz, 2H).
Example 1.38: preparation (R)-5-(4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl)-3-(methyl sulphonyl)-1,2,4-thiadiazoles (compound 37)
In bottle, add the 5-chloro-3-(methyl sulphonyl)-1 in the mixture of EtOH (1mL) and benzene (3mL); 2; the 4-thiadiazoles (125mg, 0.629mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (161mg, 0.692mmol), K
2CO
3(174mg, 1.26mmol) and two (the di-t-butyl phosphonous acid root-к P) palladates of dihydro dichloro (6mg, 0.013mmol).The gained reaction mixture was heated 60 minutes down at 100 ℃ under microwave irradiation.After finishing, inhale and shift out organic layer and use the EtOAc aqueous layer extracted.Crude mixture concentrated and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.Will be through merging the freeze-drying of pure elution part, obtain being the tfa salt (7.6mg, 5% productive rate) of the title compound of yellow oily.C
16H
21N
3O
2S
2The accurate mass calculated value: 351.1, experimental value: LCMS m/z=352.2 (M+H
+);
1H NMR (400MHz, CDCl
3) δ ppm 1.25-1.40 (m, 3H), 1.64 (d, J=6.32Hz, 3H), 1.91-2.43 (m, 4H), 2.93-3.53 (m, 5H), 3.70 (s, 1H), 4.06 (s, 1H), 7.37-7.54 (m, 2H), 8.00 (d, J=7.83Hz, 2H).
Example 1.39: preparation (R)-2-methyl isophthalic acid-(2-(4 '-((tetrahydrochysene-2H-pyrans-2-yl) methyl sulphonyl) biphenyl-4-yl) ethyl) tetramethyleneimine (compound 41)
Use 2-((4-bromophenyl alkylsulfonyl) methyl) tetrahydrochysene-2H-pyrans (185mg; 0.580mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (149mg; 0.638mmol) as initial substance; with with described in the example 1.35 step C similarly mode prepare title compound, obtain productive rate and be 35% transparent oily matter (hydrochloride).C
25H
33NO
3The accurate mass calculated value of S: 427.2, experimental value: LCMS m/z=428.3 (M+H
+);
1H NMR (400MHz, DMSO-d
6) δ ppm 1.16-1.53 (m, 7H), 1.55-1.80 (m, 3H), 1.85-2.06 (m, 2H), 2.12-2.26 (m, 1H), 3.04-3.31 (m, 5H), 3.34-3.58 (m, 4H), 3.57-3.79 (m, 3H), 7.47 (d, J=8.08Hz, 2H), 7.76 (d, J=8.34Hz, 2H), and 7.88-7.99 (m, 4H).
Example 1.40: preparation (R)-2,2-dimethyl-3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) third-1-alcohol (compound 40)
Use 3-(4-bromophenyl alkylsulfonyl)-2; 2-dimethyl propylene-1-alcohol (149mg; 0.485mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (124mg; 0.534mmol) as initial substance; with with described in the example 1.35 step C similarly mode prepare title compound, obtain productive rate and be 56% transparent oily matter (hydrochloride).C
24H
33NO
3The accurate mass calculated value of S: 415.2, experimental value: LCMS m/z=416.4 (M+H
+);
1H NMR (400MHz, CDCl
3) δ ppm 1.15-1.27 (m, 4H), 1.28-1.40 (m, 2H), 1.69 (d, J=6.57Hz, 3H), 2.00-2.18 (m, 2H), 2.23-2.42 (m, 2H), 2.89-3.10 (m, 2H), 3.11-3.39 (m, 4H), 3.47 (dd, J=12.63,3.79Hz, 1H), 3.63 (s, 1H), 3.74 (s, 1H), 4.06 (s, 1H), 4.45 (s, 1H), 7.41 (d, J=8.08Hz, 2H), 7.60 (d, J=8.08Hz, 2H), 7.77 (d, J=8.34Hz, 2H), 8.00 (t, J=9.09Hz, 2H).
Example 1.41: preparation (R)-4-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) piperidines (compound 36)
Use 4-{ (4-bromophenyl) alkylsulfonyl] piperidine hydrochlorate (150mg; 0.440mmol) and (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (113mg; 0.484mmol) as initial substance; with with described in the example 1.28 similarly mode prepare title compound, obtain productive rate and be 70% yellow oil (tfa salt).C
24H
32N
2O
2The accurate mass calculated value of S: 412.2, experimental value: LCMS m/z=413.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.32 (d, J=6.82Hz, 0.3H), 1.48 (d, J=6.32Hz, 2.7H), 1.70-1.82 (m, 1H), 1.85-1.99 (m, 2H), 2.00-2.19 (m, 2H), 2.23 (d, J=11.87Hz, 2H), 2.29-2.41 (m, 1H), and 2.95-3.36 (m, 7H), 3.45-3.71 (m, 5H), 3.72-3.83 (m, 1H), 7.48 (d, J=8.08Hz, 2H), 7.71 (d, J=8.34Hz, 2H), 7.89-8.01 (m, 4H).
Example 1.42: preparation (R)-1-(2-(4 '-(methoxymethyl alkylsulfonyl) biphenyl 4-yl) ethyl)-2-crassitude (compound 42)
Steps A: preparation (4-bromophenyl) (methoxymethyl) sulfane
To the 4-bromo thiophenol (500mg, 2.64mmol) add in the solution in THF (5mL) triethylamine (0.737mL, 5.29mmol), chloromethyl methyl ether (0.301mL, 3.97mmol).In the sealing scintillation vial, the gained mixture was stirred 2 hours down at 0 ℃.The reaction mixture dilute with water is also used the EtOAc extracting twice.Organic layer is merged, through MgSO
4Drying is filtered and is concentrated, and obtains being the title compound (585mg, 95% productive rate) of yellow oily.
1HNMR(400MHz，CDCl
3)δppm 3.47(s，3H)，4.98(s，2H)，7.33-7.41(m，2H)，7.41-7.52(m，2H)。
Step B: preparation 1-bromo-4-(methoxymethyl alkylsulfonyl) benzene
(585mg 2.51mmol) adds in the solution in THF/ water (10mL/5mL) to (4-bromophenyl) (methoxymethyl) sulfane
(1.85g, 3.01mmol).The gained mixture was at room temperature stirred 18 hours.The reactant dilute with water is also used the EtOAc extracting twice.Will be through amalgamation layer through MgSO
4Drying is filtered also and is concentrated, the title compound (610mg, 92% productive rate) of the solid state that obtains being white in color.
1H NMR(400MHz，CDCl
3)δppm3.70(s，3H)，4.54(s，2H)，7.67-7.90(m，4H)。
Step C: preparation (R)-1-(2-(4 '-(methoxymethyl alkylsulfonyl) biphenyl-4-yl) ethyl)-2-crassitude (compound 42)
In bottle, add 1-bromo-4-(methoxymethyl alkylsulfonyl) benzene (100mg in the tetrahydrofuran (THF) (4mL); 0.377mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (88mg; 0.377mmol), dicyclohexyl (2 '; 4 '; 6 '-tri isopropyl biphenyl-2-yl) phosphine (9.0mg; 0.019mmol), diacetoxy palladium (1.7mg, 7.54 μ mol) and potassiumphosphate (240mg, 1.132mmol).The gained reaction mixture was heated 60 minutes down at 100 ℃ under microwave irradiation.Dilute with water reaction mixture and isolate organic phase.Use the EtOAc aqueous layer extracted.To concentrate through merging organic layer, be dissolved in ACN/H
2Among the O (containing AcOH) and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.Elution part is merged, use 2M Na
2CO
3Alkalization and with EtOAc extraction three times.Will be through merging organic layer through MgSO
4Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (5mL).Then add HCl (1M Et
2O solution 1.65mL), adds EtOAc (5mL) then.The gained mixture is concentrated, obtain being the hydrochloride (45.1mg, 29% productive rate) of the title compound of yellow solid shape.C
21H
27NO
3The accurate mass calculated value of S: 373.2, experimental value: LCMS m/z=374.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.29 (brs, 0.3H), 1.53 (brs, 2.7H), 1.80 (brs, 1H), 2.13 (brs, 2H), 2.37 (brs, 1H), 3.08-3.42 (m, 5H), 3.50-3.70 (m, 5H), 3.80 (brs, 1H), 4.68 (s, 2H), 7.50 (brs, 2H), 7.70 (brs, 2H), 7.88 (d, J=6.57Hz, 2H), 7.98 (d, J=6.82Hz, 2H).
Example 1.43: preparation (R)-N-methyl-3-(4-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) propionic acid amide (compound 34)
Steps A: preparation 3-(4-chloro-phenyl-alkylsulfonyl) propionyl chloride
To 3-(4-chloro-phenyl-alkylsulfonyl) propionic acid (431mg, 1.73mmol) and oxalyl chloride (330mg, 0.228mL 2.60mmol) dropwise add DMF (0.3mL) in the solution in DCM (3mL).With reactant restir 45 minutes.After 45 minutes, reaction mixture is concentrated, the title compound (463mg, 100%) of the solid state that obtains being white in color, it uses without being further purified just.
1H NMR(400MHz，CDCl
3)δppm 3.36-3.44(m，2H)，3.45-3.54(m，2H)，7.63(d，J＝8.84Hz，2H)，7.89(d，J＝8.84Hz，2H)。
Step B: preparation 3-(4-chloro-phenyl-alkylsulfonyl)-N-methyl propanamide
Methylamine hydrochloride in being dissolved in water (1mL) (38mg, 0.562mmol), (331mg slowly adds 3-(4-chloro-phenyl-alkylsulfonyl) propionyl chloride (100mg, solution 0.374mmol) that is dissolved among the THF (1mL) to potassium acetate in solution 3.37mmol).Reaction mixture was at room temperature stirred 2 hours.After 2 hours, the LCMS Indicator Reaction is finished.Dilute with water reaction mixture and isolate organic phase.Use the EtOAc aqueous layer extracted.To concentrate through merging organic layer, be dissolved in ACN/H
2Among the O (containing AcOH) and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.To use 2M Na through merging elution part
2CO
3Alkalization and with EtOAc extraction three times.Will be through merging organic layer through MgSO
4Drying is filtered also and is concentrated, the title compound (26mg, 27%) of the solid state that obtains being white in color.
1H NMR(400MHz，CDCl
3)δppm 2.55-2.64(m，2H)，2.68(d，J＝4.80Hz，3H)，3.34-3.49(m，2H)，5.92(brs，1H)，7.49(d，J＝8.85Hz，2H)，7.78(d，J＝8.59Hz，2H)。
Step C: preparation (R)-N-methyl-3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) propionic acid amide (compound 34)
In bottle, add 3-(4-chloro-phenyl-the alkylsulfonyl)-N-methyl propanamide (26mg in the tetrahydrofuran (THF) (4mL); 0.099mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (23mg; 0.099mmol), dicyclohexyl (2 '; 4 '; 6 '-tri isopropyl biphenyl-2-yl) phosphine (2.4mg; 4.97 μ mol), diacetoxy palladium (0.446mg, 1.987 μ mol) and potassiumphosphate (63mg, 0.298mmol).The gained reaction mixture was heated 60 minutes down at 120 ℃ under microwave irradiation.Then inhale and shift out organic layer and use the EtOAc aqueous layer extracted.Crude mixture concentrated and by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.Will be through merging the freeze-drying of pure elution part, obtain being the tfa salt (29mg, 55% productive rate) of the title compound of yellow oily.C
23H
30N
2O
3The accurate mass calculated value of S: 414.2, experimental value: LCMS m/z=415.1 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.34 (d, J=6.82Hz, 0.3H), 1.49 (d, J=6.57Hz, 2.7H), 1.69-1.85 (m, 1H), 2.01-2.25 (m, 2H), 2.29-2.43 (m, 1H), 2.53-2.68 (m, 6H), 2.99-3.37 (m, 3H), 3.47-3.61 (m, 4H), 3.62-3.73 (m, 1H), 3.73-3.86 (m, 1H), 7.49 (d, J=8.08Hz, 2H), 7.72 (d, J=8.34Hz, 2H), 7.89 (d, J=8.59Hz, 2H), 7.99 (d, J=8.33Hz, 2H).
Example 1.44: preparation (R)-3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl)-1-morpholinyl third-1-ketone (compound 35)
Use 3-(4-chloro-phenyl-alkylsulfonyl)-1-morpholinyl third-1-ketone (20mg; 0.063mmol), (R)-4-[2-(2-methylpyrrolidin-1-yl) ethyl] phenyl-boron dihydroxide (15mg; 0.063mmol) as initial substance; with with described in the example 1.43 step C similarly mode prepare title compound, obtain productive rate and be 51% white solid (tfa salt).C
26H
34N
2O
4The accurate mass calculated value of S: 470.2, experimental value: LCMS m/z=471.6 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.34 (d, J=6.82Hz, 0.3H), 1.49 (d, J=6.56Hz, 2.7H), 1.70-1.85 (m, 1H), 2.00-2.25 (m, 2H), 2.30-2.44 (m, 1H), 2.85 (t, J=7.33Hz, 2H), 3.04-3.38 (m, 4H), 3.45-3.74 (m, 12H), and 3.73-3.85 (m, 1H), 7.49 (d, J=8.08Hz, 2H), 7.74 (d, J=8.08Hz, 2H), 7.91 (d, J=8.34Hz, 2H), 8.02 (d, J=8.34Hz, 2H).
Example 1.45: preparation (S)-1-(2-(4 '-(2-methoxy ethyl alkylsulfonyl) biphenyl-4-yl) ethyl)-2-crassitude (compound 39)
In reaction vessel, add 4-(2-chloroethyl)-4 '-(2-methoxy ethyl alkylsulfonyl) biphenyl in the acetonitrile (1mL) (75mg, 0.221mmol), yellow soda ash (70mg, 0.664mmol) and (S)-the 2-crassitude (57mg, 0.664mmol).With reaction mixture refluxed 18 hours and then filtration.Filtrate is concentrated, be dissolved among the DMSO also by HPLC (0.1%TFA in the 0.1%TFA/ water in the acetonitrile) purifying.Will be through merging the freeze-drying of elution part, the tfa salt (9.5mg, 8.5% productive rate) of the title compound of the solid state that obtains being white in color.C
22H
29NO
3The accurate mass calculated value of S: 387.19, experimental value: LCMS m/z=388.2 (M+H
+);
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.33 (d, J=6.82Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H), 1.70-1.81 (m, 1H), 2.02-2.19 (m, 2H), 2.31-2.40 (m, 1H), 3.04-3.21 (m, 5H), 3.23-3.29 (m, 2H), 3.49-3.57 (m, 3H), 3.61-3.70 (m, 1H), 3.71-3.81 (m, 3H), 7.47 (d, J=8.08Hz, 2H), 7.71 (d, J=8.08Hz, 2H), 7.86 (d, J=8.59Hz, 2H), 7.98 (d, J=8.59Hz, 2H).
Example 1.46: preparation intermediate 2-biphenyl-4-base-ethanol
Method 1: for dilution and discharge hydrogen by product, in whole process of preparation, use the nitrogen purge reactor, use the aqueous sodium hydroxide solution stopped reaction up to finishing.In the 50L reactor that contains isopropyl acetate (16.7L), add sodium borohydride (0.762kg, 20.14mol).(1L) is flushed to sodium borohydride in the reactor with extra isopropyl acetate, and makes through the stirred reactor inclusion and be cooled to 2 ℃.(2.67kg will be 12.58mol) will maintain 2 ℃-13 ℃ through the stirred reactor inclusion under the reactor jacket cooling then enough to add biphenylacetic acid lentamente.(1L) is flushed to felbinac in the reactor with extra isopropyl acetate, and makes through the stirred reactor inclusion and be cooled to-4 ℃.(3.2L, 3.584kg 25.25mol), will maintain-4 ℃ to 6 ℃ through the stirred reactor inclusion simultaneously under the reactor jacket cooling then to add boron trifluoride ethyl ether complex through two hours with constant rate of speed.Reactor content is warmed up to 20 ℃, and the LC/MS analysis discloses, and the biphenylacetic acid transformation efficiency is 95% after 19 minutes.After 16.6 hours, make it be cooled to 1 ℃ the reaction mixture stirring under 15 ℃-22 ℃.The 50 weight % solution of 6 liters sodium hydroxide in water are mixed with 9 liters of deionized waters.11 liters gained dilute hydrogen aqueous solution of sodium oxide are enough added in stirred reaction mixture lentamente under the reactor jacket cooling reactor content is maintained 1 ℃-12 ℃.The stirring under 12 ℃-20 ℃ of gained mixture also then was heated to 40 ℃ in 30 minutes.Continue down to stir 31 minutes at 40 ℃-48 ℃, and then mixture is cooled to 22 ℃.Sodium-chlor (0.50kg), deionized water (2.0L) and methyl alcohol (500mL) adding are separated with promotion in stirring the mixture.Then make respectively and be separated.Discharge water, and (4 * 5.0L) wash organic (upper strata) phases with deionized water.By vacuum distilling upper organic phase is concentrated to the 11L volume being elevated under 59 ℃ the temperature.Reactor content is cooled to 20 ℃, and adds heptane (20L).To be concentrated to the 16L volume through the stirred reactor inclusion by vacuum distilling being elevated under 36 ℃ the temperature.To be cooled to 20 ℃ through the stirred reactor inclusion, under described temperature, stir 21.4 hours, and subsequent filtration.Solid obtains title compound (2.148kg, 86.1%) with heptane (5L) washing and vacuum-drying at ambient temperature after filtration.
Method 2: (1.2g 31.7mmol) is added in containing in tetrahydrofuran (THF) (THF) flask (40mL) of stirring under the nitrogen with sodium borohydride.(5.0g 23.6mmol), will maintain under 20 ℃-30 ℃ through stirred reaction mixture simultaneously then to add biphenylacetic acid lentamente through 20 minutes.Then add THF washing fluid (5mL), and the gained mixture was stirred 20 minutes.(2.9g, the 11.4mmol) solution in THF (10mL) will maintain 20 ℃-30 ℃ through stirred reaction mixture simultaneously then to add iodine lentamente through about one hour.Continue stir about one hour under described temperature, stratographic analysis this moment discloses biphenylacetic acid and finishes conversion.Then make the reaction mixture stopped reaction by adding 5 weight % aqueous sodium hydroxide solutions (26mL).Behind gained mixture thorough mixing, make respectively to be separated, and discharge lower floor to be separated with the upper strata.With isopropyl acetate (2 * 25mL) extraction lower floor's (water) phases.Upper strata (organic) merged mutually, with deionized water (4 * 20mL) washing and vapourisation under reduced pressure, obtain being light yellow crystalline residue form 2-(biphenyl-4 '-yl) ethanol (4.6g, 98.5%).Perhaps, can be by making the product crystallization with heptane exchange isopropyl acetate described in the method 1 as mentioned.
Example 1.47: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 8)
Steps A: preparation intermediate 4 '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE
To lead to aqueous sodium hydroxide washes wash add 4 in the nitrogen purge reactor of device '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid (2.101kg (after) about 3.7 weight % water-content corrections, 7.08mol), then add thionyl chloride (5.358L, 8.74kg, 73.5mol).The gained mixture is stirred and be cooled to-2.5 ℃.(68mL, 63.7g will be 0.731mol) will maintain-3 ℃ to 0 ℃ through the stirred reactor inclusion under the reactor jacket cooling then enough to add N,N-dimethylacetamide lentamente.Reactor content is heated to 63 ℃, and continues down to stir 6.4 hours, confirm that up to analyzing initial substance is converted into product substantially fully according to LC/MS at 63 ℃-66 ℃.Reactor content is being cooled to after 19 ℃, was adding heptane (7.62L) with six equal portions through 2.5 hours.Then from product mixtures, distill out the volatile matter of mainly forming with dropping under 109 pressure that hold in the palm by thionyl chloride at 30 ℃-32 ℃.The enriched material volume is 4L.The enriched product mixture is cooled to 22 ℃, and continues down to stir 15.4 hours at 20 ℃-22 ℃.Follow the filtration product mixture.Solid is used heptane (11L) and deionized water (11L) washing (all at ambient temperature) successively after filtration, and then arrive constant weight 40 ℃ of following vacuum-dryings, obtain 4 '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE (1.664kg, 74.6% productive rate is 97.9% according to HPLC peak area purity).
Step B: preparation intermediate 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium
In the nitrogen purge reactors that contain deionized water (14.1L) that stir down at 29 ℃, add S-WAT (3.3145kg, 26.3mol), Na
2HPO
4(0.7459kg, 5.25mol) and benzyltriethylammonium chloride (65.1g, 0.265mol).Adding benzyltriethylammonium chloride makes the temperature of reactor content be elevated to 37 ℃.35 ℃-37 ℃ continue down to stir 16 minutes after all reagent all dissolve, add 4 then '-(2-chloro-ethyl)-biphenyl-4-SULPHURYL CHLORIDE (1.6584g, 5.26mol) and deionized water rinsing liquid (2.5L).Then will be elevated to 57 ℃, and under 57 ℃-60 ℃, under nitrogen, continue to stir 6 hours, and analyze the announcement initial substance up to LC/MS and transform fully through the temperature of stirred reactor inclusion.To be cooled to 42 ℃ and then filtration through stirring the mixture.To also under agitation be heated to 36 ℃ in deionized water (8.3L) the adding reactor.Then solid adds in the reactor more after filtration, and under 38 ℃ with gained mixture stirred overnight, subsequently with its filtration.At first use deionized water (3.3L) to wash solid after filtration at ambient temperature, and then with acetonitrile (being followed successively by 3.3L and 2.8L) washed twice.Will be through the washing solid 60 ℃ of following vacuum-dryings, obtain containing 4 '-(2-chloro-ethyl)-biphenyl-4-sulfonic acid (7.4HPLC area %) white thick 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium (1.2282kg, 77.1% productive rate is 92.6% according to HPLC peak area purity).
Step C: preparation 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl and 4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl
At ambient temperature to 4 '-(2-chloroethyl)-4-biphenyl-sulfinic acid sodium (217.9g, 719.7mmol), Sodium phosphate dibasic (102.2g, 719.7mmol), Tetrabutylammonium bromide (TBAB) (232.0g, 719.7mmol), Potassium Bromide (85.65g, 719.7mmol) and deionized water (809mL) in stirring the mixture, add 1-bromo-3-methoxy propane (137.7g, 899.9mmol).When the gained mixture becomes clear solution when stirring and be heated to 80 ℃ under nitrogen.After under 80 ℃ reaction mixture being stirred 16 hours, add extra 1-bromo-3-methoxy propane (12.11g, 79.1mmol).At 80 ℃ of following restir after 4 hours, add more 1-bromo-3-methoxy propanes (6.0g, 39.2mmol).Under 80 ℃, continue heating two hours (22 hours altogether) again and then stop heating.When mixture is cooled to about 65 ℃, add methyl alcohol (1.09L), and then make through stirring the mixture and be cooled to surrounding temperature whole night.The gained white depositions is filtered, and (2 * 500mL) wash and starch, air-dry and then stirring 1 hour in ethyl acetate (1.0L) at ambient temperature with deionized water.Mixture is filtered to remove TBAB by the silica gel plunger, produce yellow transparent filtrate.Under reduced pressure remove solvent, produce the yellowish white solid.Solid is used heptane at ambient temperature, and (2 * 500mL) wash and starch, and filtration is also air-dry, cause the purifying of minimum degree.To be dissolved in the dehydrated alcohol (1.0L) through the solid (294.8g) of heptane wash down at 73.4 ℃.Make through stirred solution and be cooled to surrounding temperature and then place ice-water-bath to reach 30 minutes.White solid is filtered, and (2 * 500mL) wash and starch, and then at first also follow 60 ℃ of following vacuum-dryings 9 hours in 15 hours 40 ℃ of following vacuum-dryings with ethanol.Determine that according to the HPLC peak area gained solid (178.9g, 66.0%) is 43.5%4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl and 50.6%4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl.C
18H
21ClO
3The accurate mass calculated value of S: 352.09, experimental value: LCMS m/z=353.1 (M+H
+); C
18H
21BrO
3The accurate mass calculated value of S: 396.04, experimental value: LCMS m/z (%)=397.2 (M+H
+ 78Br, 100), 399.0 (M+H
+ 80Br, 97);
1H NMR (400MHz, DMSO-d
6) δ ppm 1.72-1.83 (m, 2H), 3.07-3.13 (Cl, t, J=7.00Hz, 2H), and 3.12-3.19 (s, 3H), 3.16-3.24 (Br, t, J=7.18,2H), 3.31-3.39 (m, 4H), 3.25-3.33 (Br, t, J=7.15Hz, 2H), 3.88-3.95 (Cl, t, J=6.99Hz, 2H), 7.41-7.48 (d, J=7.09Hz, 2H), 7.69-7.74 (d, J=8.13Hz, 2H), 7.93-7.97 (m, 4H).
Step D: preparation intermediate 4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl
4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-the alkylsulfonyl)-biphenyl that at ambient temperature will be altogether prepares in the previous example of 161.8g and the mixture (being respectively 43.5% and 50.6% according to the HPLC peak area) of 4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl are dissolved in the acetonitrile (1.0L).Add TBAB (88.71g, 275.2mmol) and LiBr (95.84g 1104mmol) and with more acetonitriles (600mL is total up to 1.6L) is flushed in the reaction flask.Along with the gained mixture being stirred and under nitrogen, heating 44 hours, add extra LiBr: after 5.5 hours, add 94.75g (1091mmol) at 60 ℃-65 ℃; After 20 hours, add 99.82g (1149mmol); And after 28 hours, add 64.49g (743mmol).Then make reaction mixture be cooled to 33 ℃.The liquid phase that decant goes out reaction mixture with solids constituent from, wash solid with acetonitrile.Washing fluid is added in the supernatant liquor, and under reduced pressure remove solvent.In evaporation residue, add deionized water (1.5L).Be settled out white solid, and at ambient temperature the gained mixture stirred 1.0 hours.With solid filtering, with deionized water (3 * 500mL) washing and 40 ℃ of-45 ℃ of following vacuum-dryings 4 days.The drying solid is dissolved in the mixture of ethyl acetate (3.4L) and acetonitrile (3.1L), and filters gained solution by the silica gel plunger, (2 * 500mL) with its washing to use acetonitrile subsequently.Filtrate and washings are merged, and under reduced pressure remove solvent.With evaporation residue 45 ℃ of following vacuum-dryings; obtain white solid (160.2g; 99.0% rate of recovery), be measured as 10.7%4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl and 85.6%4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl according to the HPLC peak area.C
18H
21BrO
3The accurate mass calculated value of S: 396.04, experimental value: LCMS m/z (%)=397.2 (M+H
+ 78Br, 100), 399.0 (M+H
+ 80Br, 97);
1H NMR (400MHz, DMSO-d
6) δ ppm 1.72-1.83 (m, 2H), 3.12-3.19 (s, 3H), 3.16-3.24 (t, J=7.18Hz, 2H), 3.31-3.39 (m, 4H) 3.25-3.33 (t, J=7.15Hz, 2H), 7.41-7.48 (d, J=7.09Hz, 2H), 7.69-7.74 (d, J=8.13Hz, 2H), and 7.93-7.97 (m, 4H).
Step e: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine (compound 8)
With 4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl and 4-(2-chloro-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl (is respectively 85.55% and 9.31% according to the HPLC peak area) (198.4g; 0.499mol, based on main initial substance) transfer in the 5L three neck round-bottomed flasks that are equipped with mechanical stirrer, temp probe, condenser and nitrogen inlet.In reaction flask, add (R)-2-methylpyrrolidin-L-tartrate (95.9g), then add acetonitrile (2L).(213.9g 1.548mol), then shifts acetonitrile (380mL contains washes) to shift salt of wormwood in this mixture that stirs under nitrogen.Slurry is warmed up to 60 ℃, and adds entry (119mL) lentamente.Continue heating whole night down at 60 ℃.When not observing initial 4-(2-bromo-ethyl)-4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl according to LC/MS, with the reaction mixture cool to room temperature.By under reduced pressure distilling acetonitrile reaction mixture is concentrated.Extract with resistates water (1.2L) dilution and with ethyl acetate (2 * 600mL, then 500mL).Wash through merging organic layer with 2N HCl (2 * 600mL, then 500mL).Will through merge water layer by the ice bath cooling and with the 50%NaOH aqueous solution neutralize lentamente (keeping internal temperature within 25 ℃) also further be basified to pH 12-14.With ethyl acetate (2 * 600mL, then 500mL) extraction aqueous mixture.To have pH neutral up to washes through merging ethyl acetate layer water (2 * 600mL, then 500mL) washing, through MgSO
4Solvent is filtered and under reduced pressure removed to drying.Add heptane (300mL) and distillation to remove remaining ethyl acetate.Oiliness resistates drying under vacuum is obtained crude product (126g) whole night.Product is dissolved in the heptane (1.6L), is heated to 80 ℃ and stirred 1 hour.Be dissolved in the hot heptane product and the residual impurity that is the viscous solid shape.The solution filtered while hot is also under reduced pressure removed heptane.Resistates drying under vacuum is obtained being the product (113.2g) of light yellow waxy solid shape whole night.The HPLC of product shows 97.63% purity (according to peak area).This substance dissolves is washed in ethyl acetate (700mL) and with 2N HCl (500mL contains 15%NaCl).Separate extra 2N HCl of each layer needs (300mL) and water (being followed successively by 200mL and 100mL).With extra 2N HCl (400mL) washing organic layer.(3 * 600mL) washings are through merging water layer with ethyl acetate.The HPLC of acid water shows that product purity is 99.09% (according to peak area).With ethyl acetate (600mL) extraction and then neutralize by slow the addings 50%NaOH aqueous solution, while holding temperature under cooling off with ice bath is lower than 25 ℃ with water layer.Then water layer further is basified to pH 12-14.With ethyl acetate (2 * 600mL) extraction aqueous mixtures, and water (700mL) and 5%NaCl solution (700mL) wash acetic acid ethyl ester extract successively.Will be through merging organic phase through MgSO
4Solvent is filtered and under reduced pressure removed to drying.Resistates is suspended in the heptane of minimum volume, under reduced pressure distills out heptane.Required product is dry under vacuum, obtain light yellow waxy solid (96.7g, 48.2%).HPLC purity: 99.04% (according to peak area); Chiral analysis, 99.3%ee.C
23H
31NO
3The accurate mass calculated value of S: 401.20, experimental value: LCMS m/z=401.8 (M+H)
+, 316.8,285.2,207.1,179.8.NMR (400MHz, DMSO-d
6) δ ppm 1.02 (d, J=6Hz, 3H), 1.27 (m, 1H), 1.64 (m, 2H), 1.81 (m, 3H), 2.13 (m, 1H), 2.28 (wide m, 2H), 2.79 (m, 2H), 3.00 (m, 1H), 3.15 (m, 1H), 3.17 (s, 3H), 3.35 (m, 4H), 7.38 (d, J=8.18Hz, 2H), 7.68 (d, J=8.24Hz, 2H), 7.94 (s, 4H).
Step F: preparation (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine two Citrate trianions (compound 8)
With (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-(58.7g 0.146mol) transfers in the 1L three neck round-bottomed flasks that are equipped with mechanical stirrer and nitrogen inlet 2-methyl-tetramethyleneimine free alkali.Add acetonitrile (600mL), under nitrogen, stir the mixture, up to obtaining clear solution.(59g adds entry (29.5mL) and heats slurry down to obtain clear solution at 60 ℃ in 250mL erlenmeyer flask 0.307mol) (Erlenmeyer flask) to containing citric acid.The warm solution of citric acid is added (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl lentamente]-ethyl-acetonitrile solution of 2-methyl-tetramethyleneimine free alkali in.Use additional water (5mL) to wash erlenmeyer flask, and add in the reaction mixture.After 5 minutes, solution becomes is muddy and at room temperature mixture was stirred 1.5 hours.Filtering mixt and with solid with acetonitrile (300mL) washing and dry down in indoor vacuum (about 15 holder) under 40 ℃ in vacuum drying oven; obtain (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine two Citrate trianions (104.6g, 91%).HPLC purity is 99.15% (according to peak area).Chiral analysis, 99.5%ee.C
23H
31NO
3The accurate mass calculated value of S: 401.20, experimental value: LCMS m/z=402.0 (M+H)
+, 316.8,285.0,242.5,207.1,179.9,137.0.NMR(400MHz，DMSO-d
6)δppm 1.35(d，J＝6.48Hz，3H)，1.61(m，1H)，1.79(m，2H)，1.95(m，2H)，2.18(m，1H)，2.61(m，8H)，3.05(m，2H)，3.18(s，3H)，3.2(m，2H)，3.35(m，4H)，3.5(m，3H)，7.48(d，J＝8.24Hz，2H)，7.66(d，J＝8.24Hz，2H)，7.96(s，4H)。
Example 2: salt screening
By with compound dissolution in appropriate solvent and be distributed to and produce the free alkali stock solution in indivedual bottles.In indivedual bottles of free alkali stock solution, add the counter ion of molar excess to attempt to produce unique salt form of compound.Collect any sedimentable matter when possible and also characterize with PXRD and DSC, this is typical the first layer screening.
Example 2.1:2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-screening of the salt of ethanol (compound 10)
In ethyl acetate, THF, methyl alcohol and acetone, use following counter ion to screen 2-{4 '-[2-((R)-2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl as mentioned above }-ethanol: salt acid group, Hydrogen bromide root, phosphate radical, sulfate radical, methanesulfonic root, maltonic acid root, DL-lactate, acetate moiety, citrate, tartrate anion, malonate and malate.Isolating Citrate trianion also characterizes with PXRD and DSC.
Example 2.2:(R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-sign of 2-methyl-pyrrolidine hydrochloride (compound 3)
Characterize (R)-1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl with PXRD, DSC and TGA]-ethyl }-2-methyl-pyrrolidine hydrochloride.
Example 2.3:(R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-screening of the salt of 2-methyl-tetramethyleneimine (compound 8)
As mentioned above at ethanol; methyl alcohol; acetone; Virahol; ethyl acetate; THF; MTBE; acetonitrile; use following counter ion to screen (R)-1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl in toluene and the isopropyl acetate]-ethyl }-2-methyl-tetramethyleneimine: the salt acid group; the Hydrogen bromide root; phosphate radical; sulfate radical; the methanesulfonic root; the ethane sulfonic acid root; the Phenylsulfonic acid root; tosylate; the maltonic acid root; the DL-lactate; acetate moiety; citrate; tartrate anion and malonate.Isolating single Citrate trianion and two Citrate trianions also characterizes with PXRD, DSC, steam absorption, NMR, FTIR and HPLC.
Example 3:[
3H] N-Alpha-Methyl-histamine competitive histamine H3 receptor binding assay
Use standard laboratory program as described below to carry out the Histamine Receptors binding analysis.Use to protect wound homogenizer (polytron) tissue that homogenizes, follow contain proteinase inhibitor based on the damping fluid of HEPES in carry out differential centrifugation and prepare thick membrane portions by full rat cerebral cortex.Standby under film being chilled in-80 ℃.Frozen film is thawed and be suspended in once more in the ice-cold analysis buffer of forming by the 50mM TRIS that contains 5mM EDTA (pH=7.4).With 50 micrograms (μ g) membranin and test compounds and [
3H]-N-Alpha-Methyl-histamine (1 nmole (nM) final analysis concentration) adds in each hole of 96 hole analysis plates.That uses different concns carries (Imetit) as analyzing positive control according to wheat.At room temperature plate was cultivated 30 minutes.By using cell harvestor (perkin elmer (Perkin-Elmer)) to filter termination analysis fast with 96 hole glass fibre screen plates (GF/C).With cold analysis buffer with the film of catching washing three times and under 50 ℃ with the plate drying.Add the scintillation mixed solution of 35 microlitres (μ L) in each hole and use Top's health (TopCount) 96 orifice plate scintillometer (perkin elmer (Perkin-Elmer)) to come the recording film binding radioactivity.
Following table is showed the observation activity of some The compounds of this invention.
| Compound number | K iBinding analysis (nM) |
| Compound 1 | 2.4 |
| Compound 3 | 3.0 |
| Compound 6 | 1.1 |
| Compound 8 | 1.5 |
| Compound 17 | 16 |
In this analysis, some other The compounds of this invention has the activity value in the scope of about 750pM at about 16nM.
Example 4: rat polysomnogram (Polysomnography) scheme
Animal: with male Si Puruigeduoli (Sprague-Dawley) rat (225-350g) ((Harlan of San Diego, CA, USA city Ha Lan company, San Diego, CA)) accommodate separately and raise with 12 hours: in the controlled facility of the humidity (30%-70%) of 12 little time/dark cycle (6:30 turns on light in the morning) and temperature (20 ℃-22 ℃), it can freely take food (California, USA orange city Ha Lan-Tai Lade restaurant which serves Western food (Harlan-TekladWestern Res., Orange, CA), rodent 8604) and water.Before operation, make rat that animal facility is adapted at least three days.
Program:
With ketamine (ketamine)/xylazine (xylazine) mixture anesthetized rat, and be that EEG and EMG write down the preparation that operates.After postoperative recovery 2-3 week, make rat adapt to polypropylene test-cage at least three days.Testing the same day, rat was being placed test chamber and adaptation whole night.At some the next mornings 10, throw and test compounds to rat, it is connected with recording unit also places test chamber to reach 3 hours again.
Data analysis
In test period of three hours with EEG and EMG Data Digital and with 10 seconds timed interval storage.Follow these data visual scores, and each 10 second timed interval is characterized by non, REM sleep or awakening incident.Calculating each rat throws and or test compounds throwing and the total awakening time of back in three hour period at mediator.The awakening that then obtains each rat increases per-cent.
Following table is illustrated in the awakening of being observed after the representative compounds of oral throwing and 0.6mg/kg in 1 hour increase per-cent.
| Compound number | % awakening increase+/-s.e |
| Compound 10 | 46±15 |
Example 5: human histamine H 3 receptor binding analysis-U.S. enlightening crude drug is service company (MDS Pharma Services) (Taiwan) already
Use U.S. enlightening crude drug industry service company (MDS Pharma Services) (Taiwan) to analyze (catalog number (Cat.No.) 239810) The compounds of this invention is tested itself and human histamine H 3 receptor bonded ability.The corresponding activity value with it of some The compounds of this invention is showed in the following table.
| Compound number | Binding analysis (Ki, nM) |
| Compound 5 | 3.7 |
| Compound 7 | 2.9 |
In this analysis, some other The compounds of this invention has the activity value in the scope of about 10.1nM at about 1.7nM.
Example 6:RAMH induces the blocking-up analysis of drinking-water
When throwing with rodent, such as the reaction of R-Alpha-Methyl-histamine H3 agonist inductions such as (RAMH) drinking-water, it has susceptibility for reversing with the H3 antagonist.RAMH induces the blocking-up of drinking-water therefore can be used as the in vivo analysis of functional H3 antagonistic activity.In this analysis, light circulation (turning off the light) raisings down in 12 hours of accommodating three male Si Puruigeduoli (Sprague-Dawley) rats (250-350g) in each cage and putting upside down at 11:30.At test 10:30 on the same day, be housed in rat in the new cage individually and remove food.After 120 minutes, rat is thrown and test article (mediator or H3 antagonist, 0.3mg/kg, per os).After 30 minutes, remove water, and throwing and RAMH (mediator or RAMH, 3mg/kg salt, subcutaneous).Throwing and RAMH after 10 minutes, the water bottle of having weighed is placed cage, and animal was drunk 20 minutes.Measure the water consumption of each animal by each bottle weighed (being accurate to 0.1g).Reduce percentage according to following formula with water intake and recently represent data:
[the 1-[(antagonist/RAMH)-(mediator/RAMH)/(mediator/RAMH)-(mediator/mediator)]] * 100
| Compound number | %RAMH induces the inhibition of drinking-water |
| 2 | 82.6±12.9 |
| 7 | 92.5±15.8 |
| 15 | 58.8±16.1 |
Those skilled in the art will realize that and can be under described illustrative example be herein made various modifications, interpolation, replacement and change, and therefore think that it within the scope of the invention not departing from the situation of spirit of the present invention.All Files referred to above (including but not limited to print open case and interim and regular patent application case) is to be incorporated herein in full by reference.
Claims (56)
1. compound, it is selected from formula (Ia) compound:
With its pharmaceutically acceptable salt, hydrate and solvate;
Wherein:
R
1Be selected from the group that forms by following each group: H, C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6Haloalkyl sulfenyl, C
3-C
7Heterocyclic radical, hydroxyl, mercaptan, nitro, phenyl and sulphonamide, and each group randomly replaces through 1,2,3,4 or 5 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed; Or
R
1Together with W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through 1,2,3 or 4 substituting group, and described substituting group independently is selected from by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro, oxo base and sulphonamide are formed;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene, C
3-C
7Inferior heterocyclic radical or phenylene, each group randomly replaces through 1,2,3,4,5,6,7 or 8 substituting group, and described substituting group independently is selected from by C
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen, hydroxyl and oxo base are formed;
Ring A is the R that respectively hangs oneself
12, R
13, R
14And R
151 of replacement, 3-phenylene or 1,4-phenylene, wherein R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed; Or
Ring A is separately randomly through R
16, R
17And R
186 yuan of inferior heteroaryls or 5 yuan of inferior heteroaryls, wherein R of replacing
16, R
17And R
18Independently be selected from separately by C
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
2, R
3, R
4And R
5Independently be selected from by H, C separately
1-C
6Acyl group, C
1-C
6Acyloxy, C
2-C
8Thiazolinyl, C
1-C
6Alkoxyl group, C
1-C
8Alkyl, C
1-C
8Alkyl carboxylic acid amides, C
2-C
8Alkynyl, C
1-C
8Alkyl sulfonamide, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
1-C
8Alkyl sulfenyl, C
1-C
8Alkyl urea groups, amino, C
1-C
8Alkylamino, C
2-C
8Dialkyl amido, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, cyano group, C
3-C
7Cycloalkyl, C
2-C
8Dialkyl group carboxylic acid amides, C
2-C
8Dialkyl group sulphonamide, halogen, C
1-C
6Halogenated alkoxy, C
1-C
6Haloalkyl, C
1-C
6Haloalkyl sulfinyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6The group that haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide are formed;
R
6, R
7, R
8And R
9Independently be selected from by H, C separately
1-C
3Alkyl, C
1-C
4Alkoxyl group, carboxyl, cyano group, C
1-C
3The group that haloalkyl, halogen and hydroxyl are formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it;
Condition is:
1) ring B and R
1-W-S (O)
2The sulphur of-group not with the ring A the adjacent ring Atom Bonding; And
2) if ring A is 1,3-phenylene or 1, the 4-phenylene, and W is C
3-C
7Inferior heterocyclic radical is so with described R
1-W-S (O)
2The annular atoms of the W of the direct bond of described sulphur of-group is not a nitrogen.
2. compound according to claim 1, wherein encircling A is 1, the 3-phenylene.
3. compound according to claim 1, wherein encircling A is 1, the 4-phenylene.
4. according to the described compound of arbitrary claim, wherein R in the claim 1 to 3
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
8The group that alkyl, carboxyl and halogen are formed.
5. according to the described compound of arbitrary claim, wherein R in the claim 1 to 3
12, R
13, R
14And R
15Independently be selected from separately by H ,-CH
3, the group that forms of carboxyl, Cl and Br.
6. according to the described compound of arbitrary claim, wherein R in the claim 1 to 3
12, R
13, R
14And R
15Each is H naturally.
7. compound according to claim 1, wherein encircling A is 6 yuan of inferior heteroaryls.
8. compound according to claim 1, wherein encircling A is 5 yuan of inferior heteroaryls.
9. according to the described compound of arbitrary claim, wherein R in the claim 1 to 8
1Be selected from by H, C
1-C
6Alkoxyl group, amino, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, C
3-C
7The group that heterocyclic radical, hydroxyl and phenyl are formed, and each group is randomly through cyano group or C
3-C
7Cycloalkyl substituted; Or
R
1Together with described W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base.
10. according to the described compound of arbitrary claim, wherein R in the claim 1 to 8
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with described W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base.
11. according to the described compound of arbitrary claim, wherein R in the claim 1 to 8
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed.
12. according to the described compound of arbitrary claim, wherein R in the claim 1 to 8
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl.
13. according to the described compound of arbitrary claim in the claim 1 to 12, wherein W is C
1-C
4Alkylidene group, C
1-C
4Alkenylene, C
3-C
7Cycloalkylidene or phenylene, each group is randomly through C
1-C
3Alkyl replaces.
14. according to the described compound of arbitrary claim in the claim 1 to 12, wherein W is C
1-C
4Alkylidene group or C
2-C
4Alkenylene, each group is randomly through C
1-C
3Alkyl replaces.
15. according to the described compound of arbitrary claim in the claim 1 to 12, wherein W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed.
16. according to the described compound of arbitrary claim in the claim 1 to 12, wherein W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-and 1, the group that the 3-cyclopentylidene is formed.
17. according to the described compound of arbitrary claim in the claim 1 to 12, wherein W is selected from by-CH
2CH
2-and-group that HC=CH-forms.
18. according to the described compound of arbitrary claim, wherein R in the claim 1 to 17
2, R
3, R
4And R
5Each is H naturally.
19. according to the described compound of arbitrary claim, wherein R in the claim 1 to 18
6, R
7, R
8And R
9Each is H naturally.
20. according to the described compound of arbitrary claim, wherein R in the claim 1 to 19
10And R
11The nitrogen-atoms of both institute's bonds forms (R)-2-methyl-tetramethyleneimine-1-base together with it.
21. compound according to claim 1, it is selected from formula (Im) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
R
12, R
13, R
14And R
15Independently be selected from by H, C separately
1-C
8The group that alkyl, carboxyl and halogen are formed;
R
1Be selected from by H, C
1-C
6Alkoxyl group, amino, C
1-C
6Carbalkoxy, carboxylic acid amides, carboxyl, C
3-C
7The group that heterocyclic radical, hydroxyl and phenyl are formed, and each group is randomly through cyano group or C
3-C
7Cycloalkyl substituted; Or
R
1Together with described W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base;
W is C
1-C
4Alkylidene group, C
2-C
4Alkenylene, C
3-C
7Cycloalkylidene or phenylene, each group is randomly through C
1-C
3Alkyl replaces; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
22. compound according to claim 1, it is selected from formula (Im) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
R
12, R
13, R
14And R
15Independently be selected from separately by H ,-CH
3, the group that forms of carboxyl, Cl and Br;
R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with described W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A, and described C
5-C
7Heterocycle randomly replaces through the oxo base;
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
23. compound according to claim 1, it is selected from formula (Im) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
24. compound according to claim 1, it is selected from formula (Io) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
25. compound according to claim 1, it is selected from formula (Iq) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
R
12, R
13, R
14And R
15Each is H naturally;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
26. compound according to claim 1, it is selected from formula (Is) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
Ring A is selected from:
X is N or CH; Y is N or CH; And Z is N or CH; Condition is that at least one X, Y and Z are N;
J is N or NH; And E and G independently are selected from N or S separately, and condition is that at least one E and G are N;
R
1Be selected from by H, C
1-C
6Alkoxyl group, C
1-C
6The group that carbalkoxy, hydroxyl and phenyl are formed; Or
R
1Together with described W-SO
2Group and described W-SO
2The annular atoms of group institute bond forms C together
5-C
7Heterocycle and ring A, described thus C
5-C
7Heterocycle and shared two the adjacent ring atoms of ring A;
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH (CH
3)-,-HC=CH-, 1, the 3-cyclopentylidene ,-C (CH
3)
2CH
2-,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base, 3-tetrahydropyrans-5-base and 1, the group that the 4-phenylene is formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
27. compound according to claim 1, it is selected from formula (Is) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
Ring A is selected from:
X is N or CH; Y is N or CH; And Z is N or CH; Condition is that at least one X, Y and Z are N;
J is N or NH; And E and G independently are selected from N or S separately, and condition is that at least one E and G are N;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, the group that forms of hydroxyl and phenyl;
W is selected from by-CH
2CH
2-and-group that HC=CH-forms; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
28. compound according to claim 1, it is selected from following compound and its pharmaceutically acceptable salt, hydrate and solvate:
1-[2-(4 '-methane sulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine;
1-[2-(4 '-ethane alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine;
1-{2-[4 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
The 2-methyl isophthalic acid-2-[4 '-(propane-2-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
The 2-methyl isophthalic acid-2-[4 '-(propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
The 2-methyl isophthalic acid-[2-(4 '-phenylmethane alkylsulfonyl-biphenyl-4-yl)-ethyl]-tetramethyleneimine;
6-{4-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-1,1-dioxo-1 λ
6-sulfo-chroman-4-ketone;
1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
The 2-methyl isophthalic acid-2-[4 '-(2-methyl-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethanol;
4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl acetate;
1-{2-[4 '-(2-oxyethyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
1-[2-(4 '-ethene alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine;
1-[2-(4 '-pentamethylene alkylsulfonyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine;
3-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-third-1-alcohol;
1-{2-[3 '-(2-methoxyl group-ethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-3-alkylsulfonyl }-ethanol;
4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-tert.-butyl acetate; With
4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-methyl acetate;
Or its pharmaceutically acceptable salt, hydrate or solvate.
29. compound according to claim 28, wherein said compound are (R)-enantiomers.
30. compound according to claim 1, it is selected from formula (Is) compound and its pharmaceutically acceptable salt, hydrate and solvate:
Wherein:
Ring A is selected from by 1,4-phenylene, 1,3-phenylene, 4-carboxyl-1,3-phenylene, 4-methyl isophthalic acid, 3-phenylene, pyridine-2,5-subunit, pyrimidine-2,5-subunit and 1,2,4-thiadiazoles-3, the group that the 5-subunit is formed;
R
1Be selected from by H ,-OCH
3,-OCH
2CH
3,-C (=O) OCH
3,-C (=O) OCH
2CH
3,-C (=O) OC (CH
3)
3, group that hydroxyl, phenyl, morpholine-4-base, tetrahydrochysene-pyrans-4-base, carboxyl, 4-cyano group piperidines-1-base, amino, cyclohexyl amino, methylamino, tetrahydrochysene-pyrans-2-base is formed; Or
W is selected from by-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2-,-HC=CH-, 1, the 3-cyclopentylidene ,-CH
2C (CH
3)
2CH
2-, 4-tetrahydropyrans-2-base ,-CH
2HC=CH-,-CH
2CH
2C (=O)-,-CH
2CH (CH
3) CH
2-,-CH
2CH (CH
3)-and piperidines-2, the group that the 4-subunit is formed; And
R
10And R
11The nitrogen-atoms of both institute's bonds forms 2-methyl-tetramethyleneimine-1-base together with it.
31. compound according to claim 1, it is selected from following compound and its pharmaceutically acceptable salt, hydrate and solvate:
3-methane sulfonyl-4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-formic acid;
The 2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
2-methane sulfonyl-5-{4-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyridine;
1-{2-[4 '-(2-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
2-methane sulfonyl-5-{4-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyrimidine;
4-(2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-morpholine;
The 2-methyl isophthalic acid-2-[4 '-(tetrahydrochysene-pyrans-4-methylmethane alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
1-[2-(3 '-methane sulfonyl-4 '-methyl-biphenyl-4-yl)-ethyl]-2-methyl-tetramethyleneimine;
3-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-propionic acid;
1-(2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-piperidines-4-formonitrile HCN;
The 2-methyl isophthalic acid-2-[4 '-(third-2-alkene-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-tetramethyleneimine;
2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethamine;
Cyclohexyl-(2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-biphenyl-4-alkylsulfonyl }-ethyl)-amine;
5-methane sulfonyl-2-{4-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-phenyl }-pyridine;
N-methyl-3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) propionic acid amide;
3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl)-1-morpholinyl third-1-ketone;
4-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) piperidines;
5-(4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl)-3-(methyl sulphonyl)-1,2, the 4-thiadiazoles;
1-{2-[4 '-(3-methoxyl group-propane-1-alkylsulfonyl)-biphenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;
1-(2-(4 '-(2-methoxy ethyl alkylsulfonyl) biphenyl-4-yl) ethyl)-the 2-crassitude;
2,2-dimethyl-3-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base alkylsulfonyl) third-1-alcohol;
The 2-methyl isophthalic acid-(2-(4 '-((tetrahydrochysene-2H-pyrans-2-yl) methyl sulphonyl) biphenyl-4-yl) ethyl) tetramethyleneimine;
1-(2-(4 '-(methoxymethyl alkylsulfonyl) biphenyl-4-yl) ethyl)-the 2-crassitude;
Or its pharmaceutically acceptable salt, hydrate or solvate.
32. compound according to claim 31, wherein said compound are (R)-enantiomers.
33. a medical composition, it comprises according to described compound of arbitrary claim and pharmaceutically acceptable supporting agent in the claim 1 to 32.
34. a method for the treatment of individual histamine H 3 receptor associated conditions, its comprise to the described individuality that needs are arranged throw with treat significant quantity according to described compound of arbitrary claim or medical composition according to claim 33 in the claim 1 to 32.
35. method according to claim 34, wherein said histamine H 3 receptor associated conditions are selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders, narcolepsy, damping off, hypersomnia, somnolence syndromes, jet lag, sleep apnea or the like, attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, go up the group that air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia and alzheimer's disease (Alzheimer ' s disease) are formed.
36. method according to claim 35, wherein said histamine H 3 receptor associated conditions are sleep or Arousal disorders.
37. method according to claim 35, wherein said histamine H 3 receptor associated conditions is a cognitive disorder.
38. method according to claim 35, wherein said histamine H 3 receptor associated conditions is to damping off.
39. a method of bringing out individual awakening, its comprise to the described individuality that needs are arranged throw with treat significant quantity according to described compound of arbitrary claim or medical composition according to claim 33 in the claim 1 to 32.
40. a method for the treatment of individual pain, its comprise to the described individuality that needs are arranged throw with treat significant quantity according to described compound of arbitrary claim or medical composition according to claim 33 in the claim 1 to 32.
41. the purposes according to the described compound of arbitrary claim in the claim 1 to 32, it is the medicine that is used to make for treatment histamine H 3 receptor associated conditions.
42. according to the described purposes of claim 41, wherein said histamine H 3 receptor associated conditions is selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders, narcolepsy, dampings off, hypersomnia, somnolence syndromes, jet lag, sleep apnea or the like, attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, go up the group that air flue anaphylaxis, allergic rhinitis, nasal congestion, dementia and alzheimer's disease are formed.
43. according to the described purposes of claim 42, wherein said histamine H 3 receptor associated conditions is sleep or Arousal disorders.
44. according to the described purposes of claim 42, wherein said histamine H 3 receptor associated conditions is a cognitive disorder.
45. according to the described purposes of claim 42, wherein said histamine H 3 receptor associated conditions is to damping off.
46. the purposes according to the described compound of arbitrary claim in the claim 1 to 32, it is the medicine that is used to make for bringing out awakening.
47. the purposes according to the described compound of arbitrary claim in the claim 1 to 32, it is the medicine that is used to make for treatment pain.
48. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method by therapy for treating human body or animal body.
49. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method by the histamine H 3 receptor associated conditions of therapy for treating human body or animal body.
50. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method by the histamine H 3 receptor associated conditions of therapy for treating human body or animal body, and described histamine H 3 receptor associated conditions is selected from by cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, sleep and Arousal disorders, narcolepsy, damping off, hypersomnia, the somnolence syndromes, jet lag, sleep apnea, attention deficit Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, allergy, last air flue anaphylaxis, allergic rhinitis, nasal congestion, the group that dementia and alzheimer's disease are formed.
51. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for by the sleep of therapy for treating human body or animal body or the method for Arousal disorders.
52. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method by the cognitive disorder of therapy for treating human body or animal body.
53. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method for dampinging off by therapy for treating human body or animal body.
54. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for bringing out by therapy the method for human body or animal body awakening.
55. according to the described compound of arbitrary claim in the claim 1 to 32, it is used for the method by the pain of therapy for treating human body or animal body.
56. one kind prepares method for compositions, it comprises and will mix with pharmaceutically acceptable supporting agent according to the described compound of arbitrary claim in the claim 1 to 32.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85261006P | 2006-10-17 | 2006-10-17 | |
| US60/852,610 | 2006-10-17 | ||
| US60/934,358 | 2007-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101528684A true CN101528684A (en) | 2009-09-09 |
Family
ID=41095720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800388068A Pending CN101528684A (en) | 2006-10-17 | 2007-10-16 | Biphenyl sulfonyl and phenyl-heteroaryl sulfonyl modulators of the histamine h3-receptor useful for the treatment of disorders related thereto |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101528684A (en) |
| ZA (1) | ZA200902643B (en) |
-
2007
- 2007-10-16 CN CNA2007800388068A patent/CN101528684A/en active Pending
-
2009
- 2009-04-16 ZA ZA200902643A patent/ZA200902643B/en unknown
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| Publication number | Publication date |
|---|---|
| ZA200902643B (en) | 2010-03-31 |
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