CN1250519C - Amine derivative with K channel regulation function and its preparing process and application - Google Patents
Amine derivative with K channel regulation function and its preparing process and application Download PDFInfo
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- CN1250519C CN1250519C CN 01101656 CN01101656A CN1250519C CN 1250519 C CN1250519 C CN 1250519C CN 01101656 CN01101656 CN 01101656 CN 01101656 A CN01101656 A CN 01101656A CN 1250519 C CN1250519 C CN 1250519C
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Abstract
The present invention provides an amine derivative shown in a general formula I (disclosed in the specification), isomer, racemate, or optical isomer of the amine derivative, pharmaceutical salts, amide or ester of the amine derivative, medical composition containing the materials, the producing method of the composition, and the use of the composition for preparing medicines for preventing or treating cardiovascular diseases, diabetes, and bronchus and urinary system smooth muscle spasm, wherein the composition can be used for treating hypertension, angina pectoris, myocardial infarction, congestive heart failure, arrhythmia, diabetes, bronchus spasticity disease, bladder or ureter spasticity disease and depression.
Description
The present invention relates to be used for prevention or treatment cardiovascular disorder, diabetes, the sulfonamide derivatives of the application in the medicine of segmental bronchus and urinary system smooth muscle spasm, its steric isomer, its pharmaceutical salts, its preparation method, contain their pharmaceutical composition and be used for prevention or treatment cardiovascular disorder such as hypertension, irregular pulse, stenocardia, congestive heart failure, myocardial infarction, diabetes, segmental bronchus and urinary system smooth muscle spasm, be used to study cardiovascular as the instrument medicine, nerve and pancreatic cell potassium channel, especially adenosine triphosphate (ATP) sensitive potassium channel (K
ATP) the application of 26S Proteasome Structure and Function.
Potassium channel is one of ionic channel important in the mammalian body, and for the membrane potential of keeping excitable cell, and the histocyte normal physiological function has very important significance.Regulate the compound of potassium channel function, can be used for treating the common disease and the frequently-occurring disease of cardiovascular systemss such as hypertension, stenocardia, irregular pulse, congestive heart failure clinically, also can be used for treating diabetes, and segmental bronchus, bladder and the caused disease of ureter smooth muscle spasm.
Potassium channel mainly is divided into two big classes: a class is the electric pressure controlling potassium channel; Another kind of is the chemical regulation potassium channel.Each class potassium channel can be divided into multiple hypotype again.The function Characteristics that adopts pharmacological method research new compound has crucial meaning for the pharmacological characteristic of illustrating potassium channel and hypotype thereof for seeking new and effective clinical treatment medicine.
The ATP sensitive potassium channel belongs to the chemical regulation potassium channel, extensively be present in cardiovascular, nerve and body of gland, especially mediation important pathological or physiological role under ischemic or anoxybiotic pathological state are the important target molecules of estimating treatment hypertension, stenocardia, irregular pulse, congestive heart failure, diabetes, segmental bronchus, bladder and ureter disease that smooth muscle spasm causes.
The medicine that can regulate potassium channel is called potassium channel openers (PCO) or potassium channel activator (KCA), mainly contain: can be divided into three types from physiological action, the I type directly acts on conversion subunit, both do not relied on ATP, do not rely on nucleoside diphosphate (NDP) again, comprise Pinacidil, left-handed Crow card woods, YM-934 and A Likalin etc.; The II type acts on ATP in conjunction with suppressing site or associated site, depends on the existence of ATP, comprises ER-001533, HOE234 etc.; The III type acts on the NDP binding site, depends on NDP, as Nicoril; Can be divided into the dicyanodiamide class of replacement or Thiourea (as Pinacidil from chemical structure, ER-001533, U-94968, BRL-49074 etc.), aryl amide that replaces and derivative thereof are (as Nicoril, KRN-239, Ki-1769 etc.), benzo pyran that replaces and reworked thereof are (as left-handed Crow card woods, YM-934, Ro-31-6930, SDZ-PCO-400, UR8225 etc.), the cyclic hydrocarbon radical thioformamide class that replaces (as A Likalin etc.), the tertiary alcohol class that replaces, dihydropyridines and fused ring derivative thereof, benzimidazole thiophanate is for diazines, miazines, and other heterocyclic.At present, still there is not secondary-amine compound at the report of using aspect the adjusting potassium channel function.K
ATPAntagonist is a sulfonylureas, as Glyburide and Gludipizide etc., the cardiovascular effect that can resist the KCA medicine.Existing KCA existing problems mainly are: do not have the better tissues specificity, severe side effect is arranged, as reflex tachycardia, oedema, pained, flush, cardiac hypertrophy etc.Therefore, seek that to have more specific medicine significant.
The objective of the invention is to seek and develop new prevention or treatment cardiovascular disorder, especially prevention or treatment and potassium-channel and regulate the medicine of diseases associated.
The inventor has now found that formula I or formula I with good potassium-channel regulating effect through research extensively and profoundly
aAmino derivative, such can be used for prevention or treatment cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm.Studies show that formula I or I
aThe cardiovascular effect of sulfonamide derivatives (as influencing blood pressure, heart rate, the effect of cardiac systolic function and diastolic function) can be resisted by ATP sensitive potassium channel antagonist Glyburide.Further synthetic with studies show that. the pharmaceutical salts that the derivative that the present invention includes and suitable mineral acid or organic acid form has the function of adjusting potassium channel equally, and has a selectivity antihypertensive function, reduce the heart oxygen-consumption, the effect of the vasodilation and the adjusting rhythm of the heart.The present invention is based on and above-mentionedly find to such an extent that finish.
First aspect present invention relates to the sulfonamide derivatives shown in the general formula I, its isomer, raceme or optical isomer, its medicinal acid addition salt, its acid amides or its ester can be used for preventing or treat cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm in preparation medicine or, nerve cardiovascular as being used to study and pancreatic cell potassium channel, especially adenosine triphosphate (ATP) sensitive potassium channel (K
ATP) the instrument medicine of 26S Proteasome Structure and Function in application,
Wherein:
R
1, R
2, R
3Represent hydrogen atom, C respectively
1-20Saturated or undersaturated straight or branched aliphatic hydrocarbon, C
3-20Cycloalkyl group, replace C
3-20Cycloalkyl group, C
5-20Aryl radical, replace C
5-20Aryl radical, C
5-20Heterocycle alkyl, replacement C
5-20Heterocycle alkyl, Alpha-hydroxy C
2-20Alkyl, α-C
1-10Alkane carbonyl oxygen C
1-10Alkyl, C
6-14α-Fang carbonyl oxygen base C
1-10Alkyl, alpha-substitution C
6-14Virtue carbonyl oxygen base C
1-10Alkyl, α-C
1-10Alkoxy C
1-10Alkyl, alpha-substitution C
5-10Aryloxy C
1-10Alkyl, alpha-amino group C
1-20Alkyl, α-C
1-10Alkylamino radical C
1-10Alkyl, α-C
5-14Aryl amine C
1-10Alkyl, alpha-substitution C
5-14Aryl amine C
1-10Alkyl, α-C
1-10Alkyl amide C
1-10Alkyl, α-C
6-14Aromatic amide C
1-10Alkyl, alpha-substitution C
6-14Aromatic amide C
1-10Alkyl;
R
4Represent hydrogen atom, C
1-20Saturated fatty alkyl, C
5-20Aryl radical, replacement C
5-20Aryl radical, C
3-20Heterocycle alkyl, replacement C
3-20Heterocycle alkyl, C
3-20Heterocyclic radical, replacement C
3-20Heterocyclic radical, C
1-20Straight chain fatty acyl group, C
4-20Side chain fatty acyl group or and R
1, R
2, R
3The C that forms
3-20Cyclic hydrocarbon radical, C
3-20Heterocyclic radical, wherein said heterocycle refer to contain 1-3 and are selected from N, O or heteroatomic list of S or annelated heterocycles, and each substituting group that has substituent group is selected from: halogen, hydroxyl, cyano group, nitro, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, one, two or three halo C
1-6Alkyl, amino, C
1-10The hydroxylamine base, C
1-10Alkylacyloxy, C
6-10Aryl acyloxy or C
1-10Amide group.
Second aspect present invention relates to the general formula I that is used to prevent or treat cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm
aShown sulfonamide derivatives, its isomer, raceme or optical isomer, medicinal acid addition salt, its acid amides or its ester,
Wherein:
(1). work as R '
1Be sec.-propyl, R '
2, R '
3During for methyl, R '
4Can be sec.-propyl, normal-butyl, isobutyl-, tertiary butyl, ring third methyl, dimethylamino ethyl, allyl group, diisopropylamino ethyl; Or
(2). work as R '
1, R '
2Be methyl, R '
3-C-NH-R '
4Can be the sulfonamide derivatives shown in the following formula, its
Isomer, raceme or optical isomer,
Wherein R and R ' are C
1-5Alkyl, n are the integer of l-8; Or
(3). work as R '
1Be phenyl, R '
2During for methyl, R '
3Can be methyl, ethyl, sec.-propyl, R '
4Can be propyl group, methoxy carbonyl methyl; Or
(4). work as R '
1Be (CH
3)
2C (NH
2)-, R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1Be (CH
3)
2C (OH)-, R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-or (CH
3)
2CH (CH
3)-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-or R '
2With R '
3Be together-(CH
2)
4-or-(CH
2)
5-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1Be (CH
3)
2C (ONO
2)-, R '
2, R '
2Be CH
3-time, R '
4Be (CH
2)
2CH-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-or R '
2With R '
3Be together-(CH
2)
4-or-(CH
2)
5-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-or (CH
3)
2CH (CH
3)-; Or
Work as R '
1For
R '
2, R '
3For-(CH
2)
5-time, R '
4Be (CH
3)
2CCH (CH
3)-; Or
(5). work as R '
1Be cyclohexyl, R '
2, R '
3Be CH
3-time, R '
4For
Or
Or
Work as R '
1Be cyclopentyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4For
Or
Or
Work as R '
1Be (CH
3)
2CH-, R '
2, R '
3Be CH
3-time, R '
4For
Or
(6). work as R '
1Be (CH
3)
2CH-, R '
2, R '
3Be CH
3-time, R '
4Be Val-, Trp-, Ile-, Leu-, Phe-, O
2N-Arg-, Pro-, Leu-Val-, Trp-Trp-Trp-, (CH
3)
2CH-SO
2-, perhaps R '
4Be one of following group:
Work as R '
1Be cyclopropyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4Be Val-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3Be CH
3-time, R '
4Be Pro-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4For Pro-or
Further aspect of the present invention relates to amine biology, its isomer, raceme or optical isomer, its medicinal acid addition salt, its acid amides or its ester shown in the general formula I that is used to prevent or treat cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm
Wherein:
R
1, R
2, R
3Represent hydrogen atom, C respectively
1-20Saturated or undersaturated straight or branched aliphatic hydrocarbon, C
3-20Cycloalkyl group, replace C
3-20Cycloalkyl group, C
5-20Aryl radical, replace C
5-20Aryl radical, C
5-20Heterocycle alkyl, replacement C
5-20Heterocycle alkyl, Alpha-hydroxy C
2-20Alkyl, α-C
1-10Alkane carbonyl oxygen C
1-10Alkyl, C
6-14α-Fang carbonyl oxygen base C
1-10Alkyl, alpha-substitution C
6-14Virtue carbonyl oxygen base C
1-10Alkyl, α-C
1-10Alkoxy C
1-10Alkyl, alpha-substitution C
5-10Aryloxy C
1-10Alkyl, alpha-amino group C
1-20Alkyl, α-C
1-10Alkylamino radical C
1-10Alkyl, α-C
5-14Aryl amine C
1-10Alkyl, alpha-substitution C
5-14Aryl amine C
1-10Alkyl, α-C
1-10Alkyl amide C
1-10Alkyl, α-C
6-14Aromatic amide C
1-10Alkyl, alpha-substitution C
6-14Aromatic amide C
1-10Alkyl;
R
4Represent hydrogen atom, C
1-20Saturated fatty alkyl, C
5-20Aryl radical, replacement C
5-20Aryl radical, C
3-20Heterocycle alkyl, replacement C
3-20Heterocycle alkyl, C
3-20Heterocyclic radical, replacement C
3-20Heterocyclic radical, C
1-20Straight chain fatty acyl group, C
4-20Side chain fatty acyl group or and R
1, R
2, R
3The C that forms
3-20Cyclic hydrocarbon radical, C
3-20Heterocyclic radical, wherein said heterocycle refer to contain 1-3 and are selected from N, O or heteroatomic list of S or annelated heterocycles, and each substituting group that has substituent group is selected from: halogen, hydroxyl, cyano group, nitro, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, one, two or three halo C
1-6Alkyl, amino, C
1-10The hydroxylamine base, C
1-10Alkylacyloxy, C
6-10Aryl acyloxy or C
1-10Amide group.
Further aspect of the present invention relates to pharmaceutical composition, and it contains at least a formula I
aOr formula I sulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt, and pharmaceutical carrier or vehicle.
The invention still further relates to the method for prevention or treatment cardiovascular disorder such as hypertension, irregular pulse, stenocardia, congestive heart failure, myocardial infarction, diabetes, segmental bronchus and urinary system smooth muscle spasm, it comprises formula I or the formula I that the patient who suffers from cardiovascular disorder such as hypertension, irregular pulse, stenocardia, congestive heart failure, myocardial infarction, diabetes, segmental bronchus and urinary system smooth muscle spasm is treated significant quantity
aSulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt.
The invention still further relates to the above-mentioned formula I of preparation
aThe method of compound is with primary amine R
1' R
2' R
3' CNH
2With R
4' X in organic solvent, through being heated to 50-300 ℃ and/or be pressurized to 0.1-20MPa and react, R wherein
1', R
2', R
3' and R
4' with as defined above, X is easy leavings group such as halogen, sulfonyloxy; Described being reflected under the catalyst action carried out, and described catalyzer is disacidify agent and/or phase-transfer catalyst, and wherein, described disacidify agent is that Lewis base comprises organic bases tertiary amine and mineral alkali, and phase-transfer catalyst is ethylene glycol or polyoxyethylene glycol; Described organic solvent is toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N, accelerine or N, N-Diethyl Aniline.And primary amine R wherein
1' R
2' R
3' CNH
2Be with the same R of urea
1' R
2' R
3' the corresponding alkene of C or alcohol or the two mixture be heated to 20-200 ℃ of prepared in reaction alkyl urea R in organic acid under vitriol oil effect
1' R
2' R
3' CNHCONH
2Then, hydrolysis prepares.Wherein, described organic acid is selected from acetate, trifluoroacetic acid or methylsulfonic acid.
The present invention also provides another kind of preparation described formula I
aThe method of compounds is with primary amine R
1' R
2' R
3' CNH
2With R
4' corresponding aldehydes or ketones is at catalyzer and have/organic solvent-free in the presence of, through being heated to 30-300 ℃ and/or be pressurized to 0.1-20MPa and carry out hydrogenation, R wherein
1', R
2', R
3' and R
4' as defined above; Be reflected under the catalyzer and carried out, wherein, described catalyzer is palladium-carbon, Raney's nickel, platinum oxide and nickel-copper, and described organic solvent is and R
4' corresponding excessive aldehydes or ketones, toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, methyl alcohol or ethanol.
The present invention also provides a kind of new preparation formula I
aThe method of amine compound, be with R
1' R
2' CNHR
4' corresponding enamine or Schiff alkali or its nitrone derivative and organometallic reagent R
3' M reacts; Perhaps, will with R
1' R
2' R
3' CNR
4' corresponding enamine or Schiff alkali is through reduction or catalytic hydrogenation; Wherein, M is selected from the group that Li, Na, Mg, Al and Zn form.
Aforesaid method comprises that also the product that described reaction is obtained is through asymmetric reaction or the further step of making isomers or optical isomer that splits; Also comprise the resulting product of reaction and mineral acid or organic acid reaction, form pharmacy acceptable salt, i.e. mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic salt; Or organic acid salt, the i.e. salt of acetate, oxalic acid, citric acid, gluconic acid, succsinic acid, tartrate, tosic acid, methylsulfonic acid, phenylformic acid, lactic acid and toxilic acid.
Description of drawings
Fig. 1 represents P1075, Pinacidil, the embodiment of the invention 1 compound (be called for short compound 1) and Glyburide and [
3H] interaction of binding site in the rat artery bar of P1075 mark.
Fig. 2 represents the effect (n=8) of potassium current in 1 pair of isolating rat artery smooth muscle cell of compound.
Fig. 3 represents the effect of potassium current in 1 pair of isolating rat artery smooth muscle cell of compound, X ± SE, and n=8, * * P＜0.01 is at contrast.
According to the present invention, used term " angiocardiopathy " refers to such as hypertension, angina pectoris, myocardial infarction, congestive heart failure and arrhythmia cordis etc. among the present invention.
The compound of general formula I according to the present invention, R1Be preferably the tert-butyl group, cyclohexyl, cyclopenta, cyclobutyl, cyclopropyl, isopentyl, cyclobutyl; Perhaps, R1Be cyclohexyl, cyclopenta, cyclobutyl, cyclopropyl, isohesyl, isopentyl, isobutyl group, the isopropyl of alpha-substituted, wherein said substituting group is amino, hydroxyl, C1-10Hydroxylamine base, C1-6Oxyl, C1-10Alkylacyloxy, C6-10Aryl acyloxy, C1-10Amide groups;
R
2Or R3Preferably be respectively hydrogen atom, C1-12Chain alkylene or C3-8Cyclic hydrocarbon radical;
R
4Be preferably hydrogen atom, C1-20Saturated fat alkyl, C3-20Cycloalkyl, C1-10Acyl group, C1-10Hydroxylamine base C1-10Alkyl, C1-20Sulfoxide group, amino acid residue and the micromolecule polypeptide fragment that combines thereof, β-nitroethylene base, beta-cyano vinyl, replacement carbonyl imido grpup, C3-20Heterocyclic radical, and C4-20Heterocyclic acyl.
The compound of general formula I according to the present invention, R2、R
3More preferably be respectively methyl, ethyl, propyl group, perhaps, R2And R3Be propylidene, butylidene, pentylidene and hexylidene.
In a preferred embodiment of the invention, described R1Be isopropyl, R2Be methyl, R3Be methyl.
According to the present invention, formula IaCompound can be selected from a kind of in the group that following compound forms:
N-(1-Methylethyl)-2,3-dimethyl-2-butylamine;
N-propyl group-2,3-dimethyl-2-butylamine;
N-(2-methyl-propyl)-2,3-dimethyl-2-butylamine;
N-encircles third methyl-2,3-dimethyl-2-butylamine;
N-acrylic-2,3-dimethyl-2-butylamine;
N-(2-(two-(1-Methylethyl) amidos) ethyl)-2,3-dimethyl-2-butylamine;
N-butyl-2,3-dimethyl-2-butylamine;
N-propyl group-Alpha-Methyl amphetamine;
N-propyl group-α, the beta-dimethyl-amphetamine;
N-(3-pyridine radicals) formoxyl-2,3-dimethyl-2-butylamine;
N-valyl base-2,3-dimethyl-2-butylamine;
N-tryptophanyl-2,3-dimethyl-2-butylamine;
N-(N-nitro) arginyl--2,3-dimethyl-2-butylamine;
N-phenylalanyl-2,3-dimethyl-2-butylamine;
N-leucyl--2,3-dimethyl-2-butylamine;
N-isoleucyl--2,3-dimethyl-2-butylamine;
N-p-toluenesulfonyl-2,3-dimethyl-2-butylamine;
N-(1-Methylethyl)-2,3-dimethyl-3-hydroxyl-2-butylamine;
N-cinnamoyl-N-(1-Methylethyl)-2,3-dimethyl-2-butylamine;
N-(1-Methylethyl)-N-(2,4,5-trichloro-benzenes oxygen acetyl group)-2,3-dimethyl-2-butylamine.
According to the present invention, the acid-addition salts of formula I compound says it is inorganic acid salt example hydrochloric acid salt, sulfate, phosphate, hydrobromate for example; Or acylate such as acetate, oxalates, sal limonis, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactate and maleate; Such as N-(1-Methylethyl)-2,3-dimethyl-2-butylamine tosilate.
The invention further relates to the new general formula I that is used for prevention or Cardiovarscular, diabetes, bronchus and urinary system smooth muscle spasmaShown amine derivative, its isomers, raceme or optical isomer, medicinal acid addition salt,
Wherein:
(1). work as R '1Be isopropyl, R '2、R’
3During for methyl, R '4Can be isopropyl, normal-butyl, isobutyl group, tertiary butyl, ring third methyl, dimethylamino ethyl, pi-allyl, diisopropylamino ethyl; Or
(2). work as R '1、R’
2Be methyl, R '3-C-NH-R’
4Can be the amine derivative shown in the following formula, its
Isomers, raceme or optical isomer,
Wherein R and R ' are C1-5Alkyl, n are the integer of 1-8; Or
(3). work as R '1Be phenyl, R '2During for methyl, R '3Can be methyl, ethyl, isopropyl, R '4Can be propyl group, methoxy carbonyl methyl; Or
(4). work as R '1Be (CH3)
2C(NH
2)-，R’
2、R’
3Be CH3-time, R '4Be (CH3)
2CH-; Or
Work as R '1Be (CH3)
2C(OH)-，R’
2、R’
3Be CH3-time, R '4Be (CH3)
2CH-or (CH3)
2CH(CH
3)-; Or
Work as R '1For
R’
2、R’
3Be CH3-or R '2With R '3Be together-(CH2)
4-or-(CH2)
5-time, R '4Be (CH3)
2CH-; Or
Work as R '1Be (CH3)
2C(ONO
2)-，R’
2、R’
3Be CH3-time, R '4Be (CH3)
2CH-; Or
Work as R '1For
R’
2、R’
3Be CH3-or R '2With R '3Be together-(CH2)
4-or-(CH2)
5-time, R '4Be (CH3)
2CH-; Or
Work as R '1For
R’
2、R’
3Be CH3-time, R '4Be (CH3)
2CH-or (CH3)
2CH(CH
3)-; Or
Work as R '
1For
R '
2, R '
3For-(CH
2)
5-time, R '
4Be (CH
3)
2CCH (CH
3)-; Or
(5). work as R '
1Be cyclohexyl, R '
2, R '
3Be CH
3-time, R '
4For
Or
Or
Work as R '
1Be cyclopentyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4For
Or
Or
Work as R '
1Be (CH
3)
2CH-, R '
2, R '
3Be CH
3-time, R '
4For
Or
(6). work as R '
1Be (CH
3)
2CH-, R '
2, R '
3Be CH
3-time, R '
4Be Val-, Trp-, Ile-, Leu-, Phe-, O
2N-Arg-, Pro-, Leu-Val-, Trp-Trp-Trp-, (CH
3)
2CH-SO
2-, perhaps R '
4Be one of following group:
Or
Or
Work as R '
1Be cyclopropyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4Be Val-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3Be CH
3-time, R '
4Be Pro-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4For Pro-or
According to the present invention, formula I
aShown sulfonamide derivatives, its isomer, raceme or optical isomer, medicinal acid addition salt also have the effect that prevents or treat cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm.Its Chinese style I
aThe acid salt of sulfonamide derivatives says it is inorganic acid salt example hydrochloric acid salt, vitriol, phosphoric acid salt, hydrobromate for example; Or organic acid salt such as acetate, oxalate, lemon salt, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate, nicotinate, cinnamate or 3-hydroxy-3-methylglutaric acid salt.Preferred formula I
aThe hydrochloride of sulfonamide derivatives, maleate, tosilate, cinnamate and 3-hydroxy-3-methylglutaric acid salt.
More specifically say, in the general formula I derivative of the present invention, R
1, R
2And R
3Can be identical or different, represent hydrogen atom, C respectively
1-20Saturated or undersaturated straight or branched aliphatic hydrocarbon, C
3-20Cycloalkyl group, replace C
3-20Cycloalkyl group, C
5-20Aryl radical, replace C
5-20Aryl radical, C
5-20Heterocycle alkyl, replacement C
5-20Heterocycle alkyl, Alpha-hydroxy C
2-20Alkyl, α-C
1-10Alkane carbonyl oxygen C
1-10Alkyl, C
6-14α-Fang carbonyl oxygen base C
1-10Alkyl, alpha-substitution C
6-14Virtue carbonyl oxygen base C
1-10Alkyl, α-C
1-10Alkoxy C
1-10Alkyl, alpha-substitution C
5-10Aryloxy C
1-10Alkyl, alpha-amino group C
1-20Alkyl, α-C
1-10Alkylamino radical C
1-10Alkyl, α-C
5-14Aryl amine C
1-10Alkyl, alpha-substitution C
5-14Aryl amine C
1-10Alkyl, α-C
1-10Alkyl amide C
1-10Alkyl, α-C
6-14Aromatic amide C
1-10Alkyl, alpha-substitution C
6-14Aromatic amide C
1-10Alkyl;
R
4Representative: hydrogen atom, methyl, ethyl, n-propyl, sec.-propyl, substituted ring propyl group, substituted ring butyl, substituted ring amyl group, substituted cyclohexyl, cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, α-(1-propenyl), 2-(1-butylene base), 3-(1-butylene base), cyclopentenyl, cyclohexenyl; Or
R
4For: aryl and substituted aryl such as phenyl, substituted-phenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, 2,4-dinitrophenyl, 3,5-dinitrophenyl, 2,6-dinitrophenyl; Heterocyclic radical and substituted heterocyclic radical are as 4-pyridyl, 3-pyridyl, 3-furyl, 3-thienyl, 3-pyrryl, oxazolinyl, thiazolinyl, pyrazolinyl, Er Qing Evil quinoline base, thiazoline quinoline base, pyrazoline quinoline base, N-substituted acyl pyrazolinyl, N-substituted acyl dihydro-oxazole quinoline base, N-substituted acyl pyrrolin quinoline base, imidazolyl, substituted imidazole base; The alpha-substitution arylalkyl is as alpha-substitution arylmethyl, alpha-substitution aryl ethyl, alpha-substitution arylpropyl, alpha-substitution aryl butyl and alpha-substitution cycloalkyl aryl; Or
R
4For: natural or alpha-non-natural amino acid residue replaces natural or alpha-non-natural amino acid residue, as Ala, Val, Leu, Ile, Phe, Asn, Glu, Trp, Tyr, Pro, Ser, Thr, Hyp, Cys, Met, Asp, Lys, Arg, His, O
2N-Arg; Natural or alpha-non-natural amino acid residue replaces little peptide fragment natural or that the alpha-non-natural amino acid residue is formed, as Cys-Cys, Arg-Arg-Arg, Pro-Arg-Asp etc.; Or
R
4For: aroyl, replacement aroyl; Sulfuryl is as alkyl sulfoxide base, aryl sulfoxide group, alkyl sulfuryl, aryl sulfuryl; The substituted ethylene base is as α-aryl amine-β-nitroethylene base, alpha-aromatic-beta-cyano vinyl; Replace the carbonyl imido grpup, as N-aryl-N '-nitro-carbonyl imido grpup, N-aryl-N '-nitro methyl-carbonyl imido grpup; Or
R
4For: alkyloyl, as propionyl, butyryl radicals and isobutyryl etc.; 4-hetaroylpyrazol, as 4-pyridine formyl radical, 3-pyrroles's ethanoyl etc., 3-indoles formyl radical, 3-indyl ethanoyl, 2-pyrroyl group and 3-pyrroles's ethanoyl etc.; Replace 4-hetaroylpyrazol, as 4-(2-nitro)-pyridine formyl radical, 3-(5-nitro) pyridine formyl radical, 3-(5-hydroxyl) indoles formyl radical, 3-(5-methoxyl group) indoles ethanoyl etc.; The alkylamino radical alkyloyl, as the dimethylin ethanoyl, the dimethylin propionyl, the diethylamine ethanoyl, the diethylin propionyl, two-(sec.-propyl) amido propionyls, 2-tropyl formyl radical, 2-tropine alkene formyl radical, 3-tropyl formyl radical, 3-tropine thiazolinyl formyl radical, N-piperazine formyl radical, N-benzoyl-1-piperazine formyl radical, 1-Pyrrolidine base formyl radical, 1-Pyrrolidine base ethanoyl, 1-Pyrrolidine base propionyl, 1-hexahydropyridine base formyl radical, 1-hexahydropyridine base ethanoyl, 1-tetrahydro pyridyl propionyl, 1-hexahydropyridine base formyl radical, 1-hexahydropyridine base ethanoyl, 1-hexahydropyridine base propionyl, two-(cyclohexyl) amido ethanoyl, two-(cyclohexyl) amido propionyls, 1-(4-hydroxyl) hexahydropyridine base ethanoyl, 1-(4-hydroxyl) hexahydropyridine base propionyl etc.; The alkyl sulfoxide base is as methyl sulfoxide base, ethyl-sulfoxide base, sec.-propyl sulfoxide group and N-morpholine ethyl-sulfoxide base etc.; The alkyl sulfuryl is as methyl sulfuryl, ethyl sulfuryl, sec.-propyl sulfone and N-morpholine ethyl sulfuryl etc.; The aryl sulfuryl is as phenyl sulfuryl-3-pyridine sulfuryl, 4-pyridyl ethyl sulfuryl and p-methylphenyl sulfuryl etc.; α-aryl amine-β-nitroethylene base, as α-(3-pyridyl) amido-β-nitroethylene base, α-(4-pyridyl) amido-β-nitroethylene base, α-(6-amino-3-pyridyl) amido-β-nitroethylene base, α-(3-oil of mirbane) amido-β-nitroethylene base, α-(3-carboxyl phenyl) amido-β-nitroethylene base, α-(3-cyano-phenyl) amido-β-nitroethylene base, α-(3-trifluoromethyl) amido-β-nitroethylene base, α-(3, the 4-dihalogenated phenyl) amido-β-nitroethylene base etc.; α-aryl amine-beta-cyano vinyl, as α-(3-pyridyl) amido-beta-cyano vinyl, α-(4-pyridyl) amido-beta-cyano vinyl, α-(6-amino-3-pyridyl) amido-beta-cyano vinyl, α-(3-oil of mirbane) amido-beta-cyano vinyl, α-(3-carboxyl phenyl) amido-beta-cyano vinyl, α-(3-cyano-phenyl) amido-beta-cyano vinyl, α-(3-trifluoromethyl) amido-beta-cyano vinyl and α-(3, the 4-dihalogenated phenyl) amido-beta-cyano vinyl etc.; N-aryl-N '-nitro carbon list imido grpup is as N-(3-pyridyl)-N '-nitro-N '-carbon list imido grpup, N-(3-nitrophenyl)-N '-nitro-N '-carbon list imido grpup and N-(3-halogenophenyl)-N '-nitro-N '-carbon list imido grpup etc.; N-aryl-N '-nitro methyl-carbon list imido grpup is as N-(3-pyridyl)-N '-nitro methyl-N '-carbon list imido grpup etc.; Alpha-aromatic-β-nitroethylene base, as α-(3-pyridyl)-β-nitroethylene base, α-(4-pyridyl)-β-nitroethylene base, α-(6-amino-3-pyridyl)-β-nitroethylene base, α-(4-nitropyridine base)-β-nitroethylene base, α-(3-cyano-phenyl)-β-nitroethylene base, α-(3, the 4-dihalogenated phenyl)-β-nitroethylene base etc., alpha-aromatic-beta-cyano vinyl, as α-(3-pyridyl)-beta-cyano vinyl, α-(4-pyridyl)-beta-cyano vinyl, α-(6-amino-3-pyridyl)-beta-cyano vinyl, α-(3-nitropyridine base)-beta-cyano vinyl, α-(3-cyano-phenyl)-beta-cyano vinyl, α-(3-trifluoromethyl)-beta-cyano vinyl, and α-(3, the 4-dihalogenated phenyl)-beta-cyano vinyl etc.; Or
R
4Be α-heterocyclic substituted-β-nitroethylene substituting group and α-heterocyclic substituted-beta-cyano ethene substituting group, wherein, heterocyclic substituent can for: the 2-position is 2,2-dimethyl, spirocyclopentyl or spirocyclohexyl, 3, the 4-position is dehydrogenation or 3-hydroxyl, and the 6-position is for inhaling electric substituent 4-benzopyranyl, 4-pyrido pyranyl or 4-thieno-pyranyl; Wherein, 6-inhales electric substituting group and can be nitro, cyano group, trifluoromethyl, pentafluoroethyl group and alkylsulfonyl etc.
Work as R
1Be alkyl, cycloalkyl, alpha-aminoalkyl, alpha-amino group cycloalkyl or aryl, R
2And R
3All be alkyl or alkylidene group, R
4During for alkyl, alkylamino radical alkyl, alkylene, cycloalkyl, alkanoic acid ester or arylalkyl, preferred formula I compound-base is shown in Table 1.
Table 1 preferred formula I compound, each substituting group is an alkyl in its Chinese style
Work as R
1Be alkyl, cycloalkyl, α-amido alkyl or α-amide group cycloalkyl, R
2And R
3All be alkyl or alkylidene group, R
4During for amino acid acyl, small molecules peptide chain, sulfonic acid acyl group, aroyl, heterocyclic acyl, preferred formula I compound sees Table 2.
Table 2 preferred formula I sulfonamide derivatives has acyl substituent in its Chinese style
R
2, R
3And R
4All be alkyl or alkylidene group, R
1During for Alpha-hydroxy alkyl, Alpha-hydroxy cycloalkyl or its corresponding nitric ether, preferred substituted sees Table 3 for the formula I compound of alcohol or its ester.
The formula I compound that alcohol or its ester are arranged in table 3 substituting group
Work as R
1, R
2And R
3All be alkyl or cycloalkyl, R
4During for tetrahydroglyoxaline, thiazoline or substituted imidazoline, R
4For the formula I compound of heterocyclic radical sees Table 4.
Table 4R
4Formula I compound for heterocyclic substituent
Further, R
4Also can with R
1, R
2And R
3Constitute ring compound, such as the corresponding cyclic analogs of compound in table 1, table 2 and the table 3.As 2,2,3,5-tetramethyl-Pyrrolidine, 2,2,3,6-tetramethyl piperidine and 2,2,3,7-tetramethyl-azepan etc.
Further, formula I
aCompound also can generate derivatives such as acid amides or ester with organic acid, and preferred acid is nicotinic acid, styracin, toxilic acid, 2,4,5-trichlorophenoxyacetic acid and 3-hydroxy-3-methylglutaric acid.
According to the present invention, formula I
aThe preparation method's 1 of compound general conditions is generally: with suitable primary amine (R
1') (R
2') (R
3') CNH
2Same R
4' X is solvent-free or in containing hydrocarbon organic solvent, or aromatic organic solvents or alcoholic solvent, as hexanaphthene, pentane, hexane, heptane, octane, nonane, decane, dodecane etc., benzene, toluene, dimethylbenzene, oil of mirbane and ethylene glycol, propylene glycol, glycerol etc., in the organic solvent, at catalyst-free or there is catalyzer to comprise various organic basess or mineral alkali and organic alcohols, as KOH, NaOH, pyridine, ethylene glycol, propylene glycol, glycerol, effect such as oligomeric ethylene glycol down, through heating and or pressurization to carry out the Heating temperature scope be 50～400 ℃, preferred range is 110 ℃～250 ℃.Be reflected in the autoclave and carry out, pressure is decided with adding solvent types and Heating temperature, perhaps charges into rare gas element, as N
2, gas such as He, Ar gas, pressure is generally at 0.1～20MPa in the reaction process, the preferred pressure scope is 0.5～15MPa.The purification process of target compound can be by general recrystallization method, and perhaps chromatography is separated.As needs, can be with general formula I
aCompound and mineral acid or organic acid reaction form suitable pharmaceutical salts.
According to the present invention, formula I
aThe preparation method's 2 of compound general condition is, with primary amine R
1' R
2' R
3' CNH
2With R
4' corresponding aldehydes or ketones is at catalyzer and have/organic solvent-free in the presence of, through being heated to 30-300 ℃ and/or be pressurized to 0.1-20MPa and carry out hydrogenation, R wherein
1', R
2', R
3' and R
4' as defined above; Be reflected under the catalyzer and carried out, wherein, described catalyzer is palladium-carbon, Raney's nickel, platinum oxide and nickel-copper, and described organic solvent is and R
4' corresponding excessive aldehydes or ketones, toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, methyl alcohol and ethanol.
The preparation method of primary amine is with the same R of urea in aforesaid method
1' R
2' R
3' the corresponding alkene of C or alcohol or the two mixture be heated to 20-200 ℃ of reaction and form alkyl urea R in organic acid under vitriol oil effect
1' R
2' R
3' CNHCONH
2Then, this alkyl urea of hydrolysis prepares.Wherein, described organic acid is selected from acetate, trifluoroacetic acid or methylsulfonic acid.
In aforesaid method, when the compound of general formula I representative is an alkane secondary amine, secondary amide, and during secondary sulphonamide, can prepare by methods known in the art, referring to M.S.Dunn, B.M.Smart., Org.Synth., Coll.Vol.IV, 55 (1963); Houben-Weyl., XI/2,482; J.B.Hendrickson, R.Bergeron, Tetrahedron lett, 1973,3839; Also can again through reduction or catalytic hydrogenation, prepare secondary amine compound by imines or the Schiff alkali of forming earlier known in the art, referring to D.M.Balcom, C.R.Noller, Org.Synth., Coll Vol.IV, 603 (1963); Cesare Ferri, " Reaktionen der organischen Synthese ", Stuttgart, 1978, p85.The preparation of secondary amine compound still has special method, as with Schiff alkali or imines through the Grignard addition reaction, the secondary amine that preparation replaces, referring to Klusener P.A.A, Tipl and Brandsma, Tetrahedron 1991,2041; Klusener P.A.A, J.Chem.Soc., Chem.Commun, 1985,1677.
Secondary amine compound when the general formula I representative, mean that Alpha-hydroxy or α-amido replaces, or during the derivative of its replacement, can be raw material with epoxy compounds or ring tetrahydroform (Aziridine) derivative, with full amine through the nucleophilic ring opening prepared in reaction, referring to O.C.Dermer, G.E.Ham, Ethylenimine and other Aziridines, Academic Press, New York, 1969; L.B.Clapp, J.Amer.Chem.Soc 70,184 (1948).
In the compound of general formula I representative, R
4When representing the micromolecule polypeptide fragment that various Amino acid residues or its combine, can be by protection-condensation known in the art-deprotection or the preparation of its circulation method, referring to Ming Zhao, Chinese J.Med.Chem., 1995; 5 (2): 91, GuMingdi, Peng Shipi, Yu Xuemin, J.Chin.Pharm.Sci, 1993; 2 (2): 102.
R in the compound of general formula I representative
4During=H, be the primary amine raw material, its preparation method is generally: through the synthetic corresponding amide of Ritter reaction, hydrolysis gets then earlier.F.M.Furan and N.J.Somerville prepare the tertiary amyl urea method (US1972,3673249) of synthetic special amylamine then from corresponding alcohol.The present invention and then a kind of method for preparing the primary amine raw material is provided promptly, is heated to 20-200 ℃ of prepared in reaction alkyl urea with urea with corresponding alkene or alcohol or the mixture of the two earlier in organic acid under vitriol oil effect; Wherein, described organic acid is selected from acetate, trifluoroacetic acid or methylsulfonic acid etc.Then, hydrolysis makes corresponding primary amines under acid or alkali or other catalyst.
According to the present invention, formula I or formula I
aCompound can exist by stereoisomer form.The asymmetric center that exists in formula (I) compound can have S configuration or R configuration.The present invention includes all possible steric isomer such as enantiomorph or diastereomer, and the mixture of two or more steric isomers, for example mixture of any required ratio of enantiomorph and/or diastereomer.Therefore, the present invention relates to enantiomorph, for example left-handed-and the mixture or the racemoid of two kinds of enantiomorphs existing of dextrorotation-enantiomorph and different ratios that exists with enantiopure form.If there is suitable/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms.If desired, the preparation of single stereoisomers can split mixture according to conventional methods, or by for example synthetic preparation of three-dimensional selection.If there is the mobile hydrogen atom, the present invention also relates to the tautomeric form of formula (I) compound.
According to the present invention, formula I compound and steric isomer thereof are in prevention or treatment cardiovascular disorder such as hypertension, irregular pulse, stenocardia, congestive heart failure, myocardial infarction, diabetes, segmental bronchus and urinary system smooth muscle spasm demonstration excellent results.Therefore can be used as and prevent or treat cardiovascular disease medicine to be used for animal, be preferred for Mammals, particularly the people.
Therefore the present invention also relates at least a formula I or the formula I that contains as the effective dose of active ingredient
aCompound, or the pharmaceutical composition of its pharmaceutical salts and/or its steric isomer and conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains formula I or the formula I of 0.1-90 weight %
aCompound and/or its physiologically acceptable salt.Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, can be with formula I or formula I
aCompound and/or steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent combine, and make the suitable administration form or the dosage form that can be used as human.
Formula I of the present invention or formula I
aCompound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. for example.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, with effective constituent formula I or formula I
aCompound or its steric isomer mix with above-mentioned various carriers, and the mixture that will obtain thus places hard obviously capsule or soft capsule.Also can be with effective constituent formula I or formula I
aCompound or its steric isomer are made microcapsule, are suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, for example, water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
Formula I of the present invention or formula I
aCompound, or the dosage of its pharmaceutical salts or its steric isomer depends on many factors, for example will prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.
Embodiment
The present invention can be further specified by the following example, but these examples of implementation do not mean that any limitation of the invention.
Embodiment 1 N-(1-methylethyl)-2, the preparation of 3-dimethyl-2-butylamine-compound 1
Method one:
Get 7.6g (0.0745mol) 2,3-dimethyl-2-butanols, 32.4ml Glacial acetic acid, mixing.Bathe control with cryosel and make Nei Wenda-5 to-8 ℃, gradation adds powder solid potassium cyanide 7.3g (0.49mol), stirs.Slowly drip vitriol oil 32.4ml, temperature is below 20 ℃ in the control.Finish, in stirring 3.5 hours below 20 ℃, stirred 6 hours in room temperature again, room temperature is placed and is spent the night.Pour among the frozen water.Be neutralized to pH 10 with 20% sodium hydroxide solution, use ether extraction 4 times, spend the night with anhydrous sodium sulfate drying.Filter next day, removes siccative, steams except that behind the ether, and the decompression base leaks, and collects 105-108 ℃/5mmHg of bp fraction, gets 8.8g, and productive rate 91.6% is N-(2-(2, the 3-dimethylbutyl) methane amide.
(2-(2, the 3-dimethylbutyl) methane amide after ethanol 6.2ml and water 51.6ml mix, adds concentrated hydrochloric acid 17.4ml, refluxes 4 hours in the oil bath to get 7.7g (0.0597mol) N-.After the decompression base removed ethanol, the ice bath cooling was alkalized to more than the pH12 with 40% sodium hydroxide solution down.Use ether extraction, the Anhydrous potassium carbonate drying.After reclaiming ether, air distillation is collected bp97-104 ℃ and is leaked branch, is total to 3.75g, productive rate 62.2%.Be 2,3-dimethyl-2-butylamine.
Get 10.6g (0.15mol) 2,3-dimethyl-2-butylamine, alkane in 6.45g (0.0524mol) bromo is different, 3.0ml ethylene glycol and 22.0ml toluene place the 50.0ml autoclave, and heat is 17 hours in 170 ℃ of stirrings.Finish, tell organic layer.Divide the extraction organic layer four times with 6N hydrochloric acid 60.0ml, merge acid solution, once with toluene wash.Ice bath down with 4% sodium hydroxide alkalize to pH be 12-13, use ether extraction, the Anhydrous potassium carbonate drying.After reclaiming ether, distillation is collected 135-145 ℃ of fraction of bp, productive rate 68.8%.228-230 ℃ of (i-PrOH:Et of hydrochloride mp
2O).Ultimate analysis C
9H
22ClN (%) calculated value C 60.14, H 12.34, and N 7.79, and Cl 19.73, measured value C 60.14, H12.48, N 7.31, and Cl 19.67.
1H-NMR(D
2O，ppm)0.98(d，J＝6.75H，6H)，1.33(S，6H)，1.37(d，J＝6.46，6H)，2.10(m，1H)，3.70(m，1H)。MS(m/z)143(M
+)，100(B)。
Method two:
Getting 288ml glacial acetic acid and 412g (6.86mol) urea mixes, add 288g (3.43mol) 2,3-dimethyl-2-butylene, stir and drip the 412ml vitriol oil and 412ml glacial acetic acid mixed solution down, interior warm 45-50 ℃ of control is dripped and is finished, and stirs 5h in 50-55 ℃ again, placement is spent the night, and continues at 50-55 ℃ of reaction 7h.To the 8000ml frozen water that is dissolved with 1200g (30mol) sodium hydroxide, filter collection solid, 5 * 200ml water washing, drying gets the 404g white solid, mp 175-176 ℃, is N-(2,3-dimethyl-2-butyl) urea, productive rate 81.8%.
1H-NMR(CDCl
3，ppm)0.88-0.91(d，6H，2×CH
3)，1.26(s，6H，2×CH
3)，2.20-2.26(m，1H，CH)，4.45(br，2H)，4.65(br，1H).MS(m/z)145.0 144.0(M
+)143.0，129.1，101.0，86.1，69.1，58.0(B)。Ultimate analysis C
7H
16N
2O (%) theoretical value C 58.30, H11.18, N 19.42; Measured value C 58.70, H 11.54, and N 19.25.
Get 118g (2.95mol) sodium hydroxide, be dissolved in 118ml water, cold slightly, be added in 196g (1.36mol) N-(2,3-dimethyl-2-butyl) urea and 392ml ethylene glycol or the trolamine, in 120 ℃ of oil baths, react 8h, 95-102 ℃ of fraction collected in air distillation, adds 75g Anhydrous potassium carbonate, 40g sodium hydroxide, redistillation, collecting 99-101 ℃ of fraction, get the 88.5g colourless liquid, is 2,3-dimethyl-2-butylamine, productive rate 64.3%.
1H-NMR(CDCl
3，ppm)0.88-0.91(d，6H，2×CH
3)，1.04(s，6H，2×CH
3)，1.53(m，1H，CH)。
Get 10.6g (0.15mol) 2,3-dimethyl-2-butylamine, alkane in 6.45g (0.0524mol) bromo is different, 3.0ml ethylene glycol and 22.0ml toluene place the 50.0ml autoclave, and heat is 17 hours in 170 ℃ of stirrings.Finish, tell organic layer.Divide the extraction organic layer four times with 6N hydrochloric acid 60.0ml, merge acid solution, once with toluene wash.Ice bath down with 4% sodium hydroxide alkalize to pH be 12-13, use ether extraction, the Anhydrous potassium carbonate drying.After reclaiming ether, distillation is collected 135-145 ℃ of fraction of bp, productive rate 68.8%.228-230 ℃ of (i-PrOH:Et of hydrochloride mp
2O).Ultimate analysis C
9H
22ClN (%) calculated value C 60.14, H 12.34, and N 7.79, and Cl 19.73, measured value C 60.14, H 12.48, and N 7.31, and Cl 19.67.
1H-NMR(D
2O，ppm)0.98(d，J＝6.75H，6H)，1.33(S，6H)，1.37(d，J＝6.46，6H)，2.10(m，1H)，3.70(m，1H)。MS(m/z)143(M
+)，100(B)。
Method three:
Get the enamine that 0.1mol is made by methyl isopropyl Ketone and Isopropylamine dehydration, be dissolved in the 20ml hexane, logical N
2Under low temperature this solution is splashed into to containing in the 0.1mol lithium methide solution, ice bath stirs, and reaction is finished, and content is poured in the 0.5Kg frozen water, stirs.Water layer ether extraction secondary.Concentrate organic layer, add 3N hydrochloric acid, make pH value be lower than 1, reacted 10 minutes, with 10% sodium hydroxide alkalize to pH greater than 11.Ether extraction three times is used the Anhydrous potassium carbonate drying.Filter, underpressure distillation is collected 140-145 ℃ of cut of bp, productive rate 80%.
Embodiment 2 N-propyl group-2, the preparation of 3-dimethyl-2-butylamine-compound 5
Get the third clear 8.25g (0.15mol) and be dissolved among the ice vinegar liquid 25ml, slowly drip vitriol oil 15g for about 38 ℃, drip 2 again in interior temperature, 3-dimethyl-2-butanols 5.2g (0.051mol), interior temperature is no more than 40 ℃, the constant temperature whipping process.Pour into to frozen water,, use ether extraction with the alkalization of 40% sodium oxide.The combined ether layer washes with water once, uses anhydrous magnesium sulfate drying.Get light yellow liquid 6.2g after reclaiming ether, be dissolved among the anhydrous diethyl ether 80ml.This drips of solution is added among the anhydrous diethyl ether 80ml that contains lithium aluminum hydride 3.04g (0.08mol), refluxed again 10 hours.Cryosel cooling down, slowly drip 40% sodium hydroxide solution suitable in, carefully inclining upper strata ether liquid, with ether washing lower floor solid three times.Combined ether liquid is used the Anhydrous potassium carbonate drying.Filter, the cooling of external application ice bath, it is acid dripping anhydrous diethyl ether hydrogen chloride solution to solution.Filter collection solid is used Virahol and acetone recrystallization three times, gets white plates crystallization 3.33g, productive rate 46.33%, mp 183-185 ℃.Ultimate analysis C
9H
22NCl (%) calculated value C 10.15, H 12.34, and N 7.79; Measured value C 60.20, H 13.80, and N 7.85; MS (m/z) 143 (M
+);
1H-NMR (D
2O, ppm) 0.98 (d, 6H), 1.00 (t, 3H), 1.24 (s, 6H), 1.63 (m, 2H), 2.05 (m, 1H), 2.98 (t, 2H).
Embodiment 3 N-(1-methyl-propyl)-2, the preparation of 3-dimethyl-2-butylamine-compound 13
Press the method for example example 1.Get 2,3-dimethyl-2-butylamine and bromination Trimethylmethane prepared in reaction.Productive rate 17.1%, 203-204 ℃ of hydrochloride mp.Ultimate analysis C
10H
14NCl (%) calculated value C 61.99, H 1249, N7.23, measured value C 62.17, H13.18, N 7.27; MS (m/z) 157 (M
+);
1H-NMR (D
2O, ppm) 0.90 (d, 6H), 1.18 (t, 3H), 1.26 (d, 3H), 1.28-3.43 (m, 19H).
Embodiment 4 N-encircle third methyl-2, the preparation of 3-dimethyl-2-butylamine-compound 15
Press the method for embodiment 1, get 2,3-dimethyl-2-butylamine and brooethyl cyclopropane prepared in reaction.Productive rate 27.6%, 176-178 ℃ of hydrochloride mp.Ultimate analysis C
10H
11NCl (%) calculated value C 62.64, H 11.57, and N 7.31, measured value C 62.69, H 11.82, N 7.01.MS (m/z) 155 (M
+), 112 (M
+-43);
1H-NMR (D
2O, ppm) 0.95 (d, 6H), 1.30-3.10 (m, 14H), 5.20 (m, 1H).
Embodiment 5 N-allyl groups-2, the preparation of 3-dimethyl-2-butylamine-compound 25
Press the method for embodiment 1, get 2,3-dimethyl-2-butylamine and allyl bromide 98 prepared in reaction.Productive rate 79.3%, 173-175 ℃ of hydrochloride mp.Ultimate analysis C9H20NCl (%) calculated value C 60.80, H 11.34, and N 7.88, measured value C 60.68, H 11.43, N 7.94.MS (m/z) 141 (M
+);
1H-NMR (D
2O) 0.98 (d, 6H), 1.31 (s, 6H), 2.20 (m, 1H), 3.66 (d, 2H), 5.87 (m, 2H), 5.95 (m, 1H).
Embodiment 6 N-(2-(two (1-methylethyl) amido) ethyl)-2, the preparation of 3-dimethyl-2-butylamine-compound 27
Press the method for embodiment 1, get 2,3-dimethyl-2-butylamine and 2-(diisopropylamino) monobromoethane prepared in reaction.Productive rate 31.8%, 176-178 ℃ of hydrochloride mp.Ultimate analysis C
14H
34N
2Cl
2(%) calculated value C 55.8, and H 11.37, and N 9.3, measured value C 55.90, and H 11.68, and N 9.21.MS(m/z)229(M
+)；
1H-NMR(D
2O，ppm)1.01(d，6H)，1.38(s，6H)，1.40(d，12H)，2.04(m，1H)，3.39-3.83(m，6H)。
Embodiment 7 N-butyl-2, the preparation of 3-dimethyl-2-butylamine-compound 6
Press the method for embodiment 2, get positive fourth table nitrile and 2,3-dimethyl-2-butanols carries out the Ritter reaction, and the preparation amide intermediate is again with lithium aluminium hydride reduction preparation, productive rate 26.1%.140-142 ℃ of hydrochloride mp, ultimate analysis C
10H
24NCl (%) calculated value C 61.99, H 12.49, and N 7.23, measured value C 62.06, H 12.73, N 5.90.MS (m/z) 157 (M
+).
1H-NMR (D
2O, ppm) 0.98 (d, 6H), 1.42 (s, 6H), 1.45 (t, 3H), 1.65 (m, 6H), 2.31 (m, 1H).
The preparation of embodiment 8 N-propyl group-Alpha-Methyl amphetamine-compound 21
Press the method for embodiment 2, get propionitrile and 2-phenyl-2-butanols and carry out the Ritter reaction, the preparation amide intermediate is reduced with lithium aluminium hydride more earlier.159-161 ℃ of preparation hydrochloride mp.Ultimate analysis C
13H
22NCl (%) calculated value C 68.55, H 9.73, and N 6.15, measured value C 68.59, H 10.22, and N 5.86.MS(m/z)192(M
+)，133(M
+-C
3H
8N)；
1H-NMR(D
2O，ppm)0.83(m，6H，2CH
3)，1.58(m，2H，CH
2)，1.78(s，3H，CH
3)，2.05(m，1H，CH)，2.29(m，1H，CH)，2.53(m，1H，CH)，2.85(m，1H，CH)，7.54(m，5H，Ar-H)
Embodiment 9 N-propyl group-α, the preparation of beta-dimethyl-amphetamine-compound 19
Press the method for embodiment 2, get propionitrile and 2-phenyl-3-methyl-2-butanols and carry out the Ritter reaction, the preparation amide intermediate is reduced with lithium aluminium hydride more earlier.190-192 ℃ of preparation hydrochloride mp.Ultimate analysis C
14H
24NCl (%) calculated value C 69.54, H 10.0, and N 5.79, measured value C 69.43, H 10.40, N 5.41.MS (m/z) 206 (M
+), 147 (M
+-C
3H
8N);
1H-NMR (D
2O, ppm) 0.98 (t, 3H, CH
3), 1.28 (s, 3H, CH
3), 1.39 (t, 6H, 2CH
3), 1.63 (m, 2H, CH
2), 3.98 (m, 1H, CH), 3.12-3.28 (m, 2H, CH
2), 7.43 (m, 5H, Ar-H).
Embodiment 10 N-(3-pyridyl) formyl radical-2, the preparation of 3-dimethyl-2-butylamine-compound 39
Press the method for embodiment 2, get 3-pyridine carbonitrile and 2,3-dimethyl-2-butylene carries out the Ritter reaction.Mp166-168 ℃ of preparation hydrochloride, ultimate analysis C
12H
19ClN
2O (%) calculated value C 59.36, H 7.89, and N 11.54, measured value C 59.33, H 7.98, and N 11.45.MS(m/z)207(M
+)106(M
+-C
6H
14N)；
1H-NMR(D
2O，ppm)0.92(d，6H，2CH
3)，1.42(s，6H，2CH
3)，2.42(m，1H，CH)，8.13(q，1H，ArH)，8.86(m，2H，ArH)，9.08(s，1H，ArH).
Embodiment 11 N-figured silk fabrics amine acyl groups-2, the preparation of 3-dimethyl-2-butylamine-compound 37
Get Val-Boc 0.434g (2mmol), be dissolved among the anhydrous tetrahydro furan 2.5ml, add 2,3-dimethyl-2-butylamine 0.200g (2mmol), HOBt 0.135g (1mmol), it is molten entirely to be stirred to solid.Ice bath cooling is dissolved in the solution of tetrahydrofuran (THF) 2.5ml with DCC 0.412g (2mmol) down, drops among the above-mentioned stirring liquid, stirs 4h, and placement is spent the night.The decompressing and extracting solvent gets white solid, adds ethyl acetate 7.5ml, makes solid molten entirely.With the aqueous acid washing secondary of unsaturated carbonate hydracid sodium water solution and saturated lemon, wash secondary again with water successively to neutral, with anhydrous magnesium sulfate drying.Filter,, drip the about 5ml of anhydrous ether solution of hydrogenchloride, shake up the back and place 5h, jolting therebetween 4 times in room temperature with ethyl acetate 7ml washing secondary.Take out ether in room temperature, remove ethyl acetate under reduced pressure with warm water bath again, get the white plates solid, add anhydrous diethyl ether 10ml, stir, remove ether again under reduced pressure, get the 0.324g solid.With dehydrated alcohol and vinyl acetic monomer recrystallization, get 0.165g, productive rate 35%, 240-241 ℃ of hydrochloride mp after the drying.Ultimate analysis C
11H
25ClN
2O (%) calculated value C 55.80, H 10.64, and N 11.83, and example value C 55.85, and H 10.71, and N 11.63; MS (m/z) 201.0 (M
+).
Embodiment 12 N-tryptamines acyl groups-2, the preparation of 3-diformazan-2-butylamine-compound 40
By implementing just 11 method, get Trp-Boc under the DCC effect with 2,3-dimethyl-2-butylamine condensation prepared.Productive rate 17.5%, 135-137 ℃ of hydrochloride mp (dehydrated alcohol/ethyl acetate/anhydrous diethyl ether).MS(m/z)287(M
+)。
Embodiment 13 N-(N-nitro arginyl)-2, the preparation of 3-dimethyl-2-butylamine-compound 44
Press the method for embodiment 11, get Arg (NO
2)-Boc is in the presence of DCC, and with 2,3-dimethyl-2-closes preparation in butylamine side.Productive rate 36.4%, hydrochloride mp 175 (d) (dehydrated alcohol/ethyl acetate); MS (m/z) 302 (M
+).
Embodiment 14 N-phenylalanyls-2, the preparation of 3-dimethyl-2-butylamine-compound 43
Press the method for embodiment 11, get Pha-Boc in the presence of DCC, with 2,3-dimethyl-2-butylamine condensation prepared.Productive rate 21.8%, hydrochloride mp232-233 ℃ (dehydrated alcohol/anhydrous diethyl ether).MS(m/z)248(M
+)。
Embodiment 15 N-leucyls-2, the preparation of 3-dimethyl-2-butylamine-compound 42
Press the method for embodiment 11, get Leu-Boc in the presence of DCC, with 2,3-dimethyl-2-butylamine condensation prepared.250-252 ℃ of hydrochloride mp (dehydrated alcohol/anhydrous diethyl ether).MS(m/z)214(M
+)。
Embodiment 16 N-isoleucyl-2, the preparation of 3-dimethyl-2-butylamine-compound 41
Press the method for embodiment 11, get Ile-Boc in the presence of DCC, with 2,3-dimethyl-2-butylamine condensation prepared.246-248 ℃ of hydrochloride mp (dehydrated alcohol/anhydrous diethyl ether).MS(m/z)214(M
+)。
Embodiment 17 N-p-toluenesulfonyls-2, the preparation of 3-dimethyl-2-butylamine-compound 38
With 2,3-dimethyl-2-butylamine 1.2 grams (0.012mol), reach the 20ml pyridine and place reaction flask, the ice-water bath cooling slowly is added dropwise to the 20ml pyridine solution of 1.9 gram (0.01mol) Tosyl chlorides down, reaction solution is a yellowly, frozen water stirs 3h, stirring at room reaction 1 hour, heating, stirring reaction 2h under the temperature outside 95～100 ℃, reaction solution still is pale brown look transparence, removes solvent under reduced pressure, adds toluene, the evaporated under reduced pressure solvent, add suitable quantity of water, can all dissolve methylbenzene extraction 4 times, water is counter carries benzene liquid once, anhydrous MgSO
4Dry benzene liquid filters, and steaming desolventizes, recrystallization in Virahol, colourless column crystallization 1.1 grams, mp 80-89 ℃, recrystallization in Virahol again, white crystals shape solid 0.8 gram, mp 88-89 ℃.Ultimate analysis C
13H
21NO
2S (%): theoretical value C 61.14, and H 8.29, and N 5.48, experimental value C 61.11, and H 8.37, and N 5.55; MS (m/z) 255 (M
+), 172 (B);
1H-NMR (CDCl
3, ppm) 0.91 (d, J=6.8Hz, 6H, 2CH
3), 1.17 (S, 6H, 2CH
3), 1.82 (M, 1H, CH), 2.47 (S, 3H, CH
3), 7.32 (d, J=8.0,2H, 2Ar-H), 7.82 (d, J=8.0,2H, 2Ar-H ').
Embodiment 18 N-(1-methylethyl)-2, the preparation of 3-dimethyl-3-hydroxyl-2-butylamine-compound 58
Get 2,3-dimethyl-2,3-oxyethane 41.8g (0.418mol), 2-propylamine 20.0g (0.33mol) and toluene 50ml placed autoclave, in 170 ℃ of heated and stirred 48 hours.After being chilled to room temperature, open still.With 6N hydrochloric acid soln 100ml, divide three extractions.Merge acid solution, wash in right amount with toluene, again with 40% oxychlorination sodaization to pH be 12.Oil float is arranged in liquid level.Use ether 150ml, divide three extractions.Combined ether liquid is used the Anhydrous potassium carbonate drying.Filter, reclaim ether to doing.Bp 60-65/10mmHg cut is collected in underpressure distillation, gets 2-(N-2-methylethyl)-3-hydroxyl-2, the 3-dimethyl butylamine.156-158 ℃ of hydrochloride mp (dehydrated alcohol/anhydrous diethyl ether).Ultimate analysis C
9H
22ClNO (%) calculated value C 55.23, H 11.33, and N 7.16, measured value C55.23, H 11.65, and N 6.95; MS (m/z) 160 (M
+);
1H-NMR (CDCl
3, ppm), 1.33 (s, 6H, 2CH
3), 1.41 (d, 6H, 2CH
3), 1.42 (s, 6H, 2CH
3), 3.81 (m, 1H, CH).
Embodiment 19 N-(1-methylethyl)-2, the preparation of 3-methyl-2-butylamine tosilate
Anhydrous tosic acid: get the tosic acid that contains crystal water, in 110 ℃ of heat fused, simultaneously water is steamed, be heated to till anhydrous the steaming, cooling is placed standby in moisture eliminator.
Get the anhydrous tosic acid of 0.60g (3.5mmol), be dissolved in few dehydrated alcohol of trying one's best, under agitation splash into and be dissolved with 0.55g (0.38mmol) N-(1-methylethyl)-2, the 10mL anhydrous ether solution of 3-dimethyl-2-butylamine drips and finishes, and placement is spent the night; Then, boil off solvent, solid gets colorless solid 1.07g, mp 119-120 ℃ with the dehydrated alcohol thorough washing.
1H-NMR(D
2O，ppm)：0.96(d，6H，2CH
3)，1.303(s，6H，2CH
3)，1.36(d，6H，2CH
3)，2.02-2.15(m，1H，CH)，2.401(s，3H，CH
3)，3.62-3.73(m，1H，CH)，7.38(d，2H，2Ar-H)，7.70(d，2H，2Ar-H’)。
Embodiment 20 N-(1-methylethyl)-2, the preparation of 3-methyl-2-butylamine hydrochloride
Take by weighing N-(1-methylethyl)-2,3-dimethyl-2-butylamine 100.0g, be dissolved in 200mL ethanol, frozen water cools off and shakes down and adds 100mL hydrochloric acid, and the pressure reducing and steaming solvent is added ethanol to doing then, evaporated under reduced pressure again, then with 1: 1 Virahol-hexanaphthene recrystallization, get colorless solid 130.5g (95.5%), mp 228-230 ℃ (i-PrOH:Et
2O).Ultimate analysis C
9H
22ClN (%) calculated value C 60.14, H 12.34, and N 7.79, and Cl 19.73, measured value C 60.14, H 12.48, and N 7.31, and Cl 19.67.
1H-NMR(D
2O，ppm)0.98(d，J＝6.75H，6H)，1.33(S，6H)，1.37(d，J＝6.46，6H)，2.10(m，1H)，3.70(m，1H)。MS(m/z)143(M
+)，100(B)。
Embodiment 21 N-(1-methylethyl)-N-(2,4,5-trichlorobenzene oxygen ethanoyl)-2, the preparation of 3-dimethyl-2-butylamine
2,4,5-trichlorine phenoxyacetyl chloride: 2,4,5-trichlorophenoxyacetic acid 51.3g and sulfur oxychloride 18mL, stirring and refluxing reaction 2.5h adds a small amount of dry benzene, changes reflux into water distilling apparatus, remove excessive sulfur oxychloride and benzene under reduced pressure, solid is promptly separated out in cooling, places standby.
Add N-(1-methylethyl)-2 in the reaction flask, 3-methyl-2-butylamine. hydrochloride 1.81g, triethylamine 3.30g, the 4-dimethylamino pyridine of catalytic amount and toluene 50mL, under agitation splash into and be dissolved with 2,4, the 20mL toluene solution of 5-trichlorine phenoxyacetyl chloride 5.50g, drip and finish, heated and stirred reaction 14h in 80 ℃ of oil baths, cooling then, filter, the toluene wash solid, combining methylbenzene solution is successively with water 50mL, 1N NaOH (50mL * 2), water 50mL, 1N HCl (50mL * 2) and water 50mL washing, anhydrous sodium sulfate drying, get brown thick liquid, silica gel column chromatography gets light yellow semi-solid 3.30g (86.8%).
1H-NMR(CDCl
3，ppm)0.865(d，J＝6.75Hz，6H)，1.401(S，6H)，1.448(d，J＝6.75Hz，6H)，2.85(m，1H)，3.98(m，1H)，4.740(s，2H)，6.928(s，1H)，7.441(s，1H)。MS (m/z) EI
+: 338/336 (1: 1, (M-i-Pr)
+), 298/296 (M-thexyl)
+/ 294,84 (B, C
6H
12 +); FAB
+: 378.2/380.2 (M+H)
+/ 382.2, and 336.2/338.2 (1: 1, (M-i-Pr)
+), 296.1/298.1 (B, M+H-C
6H
12), 100.1 (special hexylamines)
+, 85.1 (C
6H
13 +).
Following biological activity test is used for further specifying the present invention.
Biological effect experiment 1 on the rat of vetanarcol anesthesia 16 formula I of the present invention compound to the influence of blood pressure, heart rate and heart systolic and diastolic function
The structure of table 5 formula I compound of the present invention and the biological activity aspect cardiovascular thereof
| Compound | R 1 | R 2 | R 3 | R 4 | SBP | DBP | MBP | HR | LVSP | -dp | Vpm | |
| 2 3 | (CH 3) 2CH- (CH 3) 2CH- | CH 3- CH 3- | CH 3- CH 3- | H- CH 3- | 38 29 | 15 19 | 24 22 | 20 43 | 116 111 | 54 157 | 1.16 0.49 |
| 4 5 6 7 8 9 10 11 12 40 41 42 43 44 | (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- H- C 2H 5- C 2H 5- C 2H 5- C 2H 5- (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- | CH 3- CH 3- CH 3- CH 3- H- CH 3- CH 3- CH 3- CH 3- CH 3- CH 3- CH 3- CH 3- CH 3- | CH 3- CH 3- CH 3- H- H- CH 3- H- CH 3- H- CH 3- CH 3- CH 3- CH 3- CH 3- | C 2H 5- n-C 3H 7- n-C 4H 9- (CH 3) 2CH- (CH 3) 2CH- (CH 3) 2CH- H- CH 3- H- Trp- Ile- Leu- Phe- O 2N-Arg- | 31 34 61 34 28 50 2 18 25 +2 +2 +2 +3 +5 | 23 25 43 34 24 36 5 10 23 0 +1 +2 +1 +6 | 25 28 49 34 26 40 4 13 24 +0.7 +1 +2 +2 +5.7 | 44 78 111 46 53 108 20 19 39 6 16 +1 +10 3 | 146 162 263 184 121 260 21 +159 112 +23 +4 +10 +31 +6 | 177 187 276 226 124 245 27 +86 129 +6 +2 +13 +10 +6 | 0.45 0.58 0.98 1.08 1.45 1.68 0.25 0.1 0.58 +0.1 0 +0.1 8 +0.1 3 +0.0 7 |
Annotate: compound is all through vena femoralis injection, dosage (unit is mg/kg), 1
#(0.5), 2
#(10), 3
#(5), 4
#(5), 5
#(5), 6
#(5), 7
#(5), 8
#(10), 9
#(5), 10
#(5), 11
#(5), 12
#(10), 40
#(5), 41
#(5), 42
#(5), 43
#(5), 44
#(5). SBP is a systolic pressure in the table, and DBP is a diastolic pressure, and MBP is a mean arterial pressure, and HR is a heart rate, and LVSP is a left ventricular systolic pressure, and-dp/dtmax is the maximum rate of change of left ventricular pressure downcomer, and Vpm is that cardiac muscle fibre shortens the speed physiological value.Data are 3-5 zooperal mean value in the table, the increase of numerical value after the+expression medication, and other data are the minimizing value after the medication.
Above result shows that compound 2～12 all can bring high blood pressure down, reducing heart rate, and the contraction and the diastolic function of inhibition heart can be used for hypertension clinically, bring high blood pressure down treatment tachycardia type irregular pulse, and treatment stenocardia and myocardial ischemia disease; The compound 40-44 blood pressure that can raise speeds heart rate, strengthens the contraction and the diastolic function of heart, the clinical treatment shock that can be used for, rising blood pressure, treatment bradyrhythmia type irregular pulse, and disease such as treatment congestive heart failure.
The research method of biological effect embodiment 1, male Wistar rat, body weight 280 ± 30g is provided by Military Medical Science Institute's Experimental Animal Center.Rat is anaesthetized through abdominal injection vetanarcol 45mg/kg, the promoting the circulation of qi cannula, and right femoral artery and femoral vein insert PE
50Polyethylene catheter, ductus arteriosus are led physiograph by MPU-0.5A type pressure transducer with RM-6000 type four and are linked to each other, record SBP, DBP, MBP, and femoral venous catheter is used for administration.Go into PE through right common carotid artery to the left ventricle interpolation
50Conduit connects pressure transducer, and signal inputs to SMUP-PC bio signal treatment system, writes down HR automatically, LVSP ,+dp/dtmax ,-dp/dtmax, indexs such as Vpm.Experimental technique sees reference for details: remember luxuriant, Wang Hai, Xiao Wenbin. Pinacidil and nifedipine are to the influence of rat heart function. institute of Military Medical Science Institute periodical, 1996; (4): 245～248.
The acute reduced pressure experiment of biological effect experiment 2 compound 1 on clear-headed spontaneous hypertensive rat.
The influence of 1 pair of Hypertensive Rats systolic pressure of table 6 The compounds of this invention
| Medicine and dosage thereof (mg/kg po) | The systolic pressure basic value | Different time after the administration (hour) rat systolic pressure (mmHg) | ||||||
| 1 | 3 | 5 | 9 | 12 | 24 | |||
| Control compound 1 Pinacidil nifedipine | 3 3 10 60 40 | 239±11 246±11 242±5 242±5 242±5 243±4 | 239±14 227±12 ***208±5 ***186±6 ***211±7 ***207±9 *** | 238±14 218±7 ***236±5 *219±12 *240±7 213±11 ** | 240±9 215±15 ***241±4 235±5 242±4 233±10 * | 242±9 229±8 * 242±5 240±6 242±3 242±4 | 243±12 243±7 244±5 242±4 243±3 241±5 | 245±11 244±19 244±5 242±4 242±6 243±4 |
Data go up the mean+SD of calculating with 9～13 rats and represent.With administration contrast, * P＜0.05, * * P＜0.01, * * * P＜0.001, own control t check.
The influence of 1 pair of Hypertensive Rats heart rate of table 7 compound
| Medicine and dosage thereof (mg/kg po) | The heart rate basic value | Different time after the administration (hour) the rat heart rate (inferior/minute) | ||||||
| 1 | 3 | 5 | 9 | 12 | 24 | |||
| Control compound 1 | 3 3 | 402±34 419±20 351±19 | 405±31 414±27 421±17 *** | 419±15 412±27 400±15 ** | 388±30 408±25 354±14 | 393±26 407±21 365±16 | 404±32 413±15 352±20 | 395±26 417±12 365±15 |
| Nifedipine Bi Suoluoer captopril | 10 60 40 | 352±19 355±17 350±17 | 410±11 *** 283±17 *** 380±12 *** | 410±31 **278±16 ***370±24 * | 367±24 335±34 366±22 * | 365±13 320±36 355±12 | 365±16 341±28 355±29 | 364±22 360±7 364±12 |
Data go up the mean+SD of calculating with 9～13 rats and represent.With administration contrast, * P＜0.05, * * P＜0.01, * * * P＜0.001, own control t check.
Above result shows, the antihypertensive function that oral administration of compound 1 produces is definite, steadily, the time length reaches 9h, waiting under the hypotensive dose and ATP sensitive potassium channel opener Pinacidil, the calcium antagonist nifedipine, beta antagonists Bi Suoluoer compares with angiotensin transferase inhibitor captopril, compound 1 step-down longer duration is light to the influence of heart rate.
The research method of biological effect experiment 2 adopts non-invasive cover tail method to measure blood pressure and heart rate.Operation steps sees document for details: Long Chaoliang, Wang Hai, Xiao Wenbin.Pinacidil is to the influence of hypertension vascular remodeling. Chinese J Pharmacol Toxicol, 1997; 11 (1): 42-46. Yin is vast, Ye Zhiwen, a left side and ring, Lou Ailin. the development of rat tail arterial blood pressure and heart rate measurement instrument. and China-Japan Friendship Hospital's journal, 1991; 5 (4): 252-253.
Biological effect is tested 3 selectivity ATP sensitive potassium channel antagonist Glyburides to formula I of the present invention
aThe antagonistic effect of the cardiovascular effect of representative compounds
Table 8 selectivity ATP sensitive potassium channel antagonist Glyburide is to the antagonistic effect of new compound 1 cardiovascular effect
| Pinacidil (n=8) | Glyburide+pyrrole row ground thats (n=6) | Nifedipine (n=5) | Glyburide+nifedipine (n=5) | Compound 1 (n=8) | Glyburide+compound 1 (n=7) | |||||||
| Before the administration | After the administration | Before the administration | After the administration | Before the administration | After the administration | Before the administration | After the administration | Before the administration | After the administration | Before the administration | After the administration | |
| SB(mmHg) DBP(mmHg) MBP(mmHg) HR(bpm) LVSP(mmHg) *dp/dtmax(kPa/a) -dp/dtmax(k±Pa/a) Vpm(/a) | 128±5 92±5 104±5 353±17 124±6 673±28 536±42 4.3±0.5 | 91±8 ** 67±6 *** 76±7 ** 317±25 * 111±9 * 571±33 * 447±73 4.1±0.5 | 142±7 95±4 110±5 322±14 127±8 725±66 584±70 6.1±0.2 | 137±4 94±3 108±3 303±17 131±5 766±37 602±38 6.6±0.1 | 144±7 95±8 111±7 335±14 131±6 761±38 650±26 5.7±0.1 | 104+8 *** 62±7 *** 76±8 *** 296±22 113±7 *** 626±57 ** 470±40 *** 4.2±0.5 | 136±4 95±6 108±5 308±12 130±10 766±73 631±88 6.4±0.7 | 104±3 ** 62±4 ** 75±3 ** 273±16 115±8 ** 649±81 * 471±44 * 4.2±1.0 * | 134±8 98±7 110±7 394±13 180±10 978±54 819±56 3.3±0.2 | 105±10 * 77±9 ** 86±9 ** 357±18 133±6 672±36 *** 507±39 *** 2.7±0.3 ** | 140±6 115±3 123±3 368±18 151±6 803±51 595±43 6.1±0.6 | 132±7 1094±4 116±5 353±21 139±6 723±51 * 541±24 5.6±0.5 |
Pinacidil 1.0mg/kg, nifedipine 1.0mg/kg, the quiet notes of compound 1 0.5mg/kg, Glyburide 20mg/kg is 10 minutes quiet in advance notes in advance, respectively at behind the quiet notes Pinacidil 30 minutes, behind the quiet notes nifedipine 10 minutes, quiet notes compound 1 was measured each parameter in the table in back 15 minutes.Data are represented with mean value ± standard error.Own control t checked * P＜0.05, * * P＜0.01, * * * P＜0.001 before and after administration was adopted in data analysis.
Above result shows that 1 pair of cardiovascular effect such as blood pressure, heart rate, heart contraction and effects on diastolic function of compound can be resisted by Glyburide.Under the same terms, selectivity ATP sensitive potassium channel antagonist Glyburide can resist the cardiovascular effect of ATP-sensitive potassium channel activator Pinacidil, but does not influence the effect of calcium-channel antagonists nifedipine.Prompting compound 1 possesses the pharmacological characteristic of cardiovascular ATP-sensitive potassium channel activator.The method of this experiment 3 is identical with the method for biological effect experiment 1.
Biological effect is tested the allosteric regulating effect of 4 new compounds to vascular smooth muscle ATP sensitive potassium channel
Table 9 compound 1 to [
3H]-Glyburide combines and the effect of kinetics of dissociating with vascular smooth muscle ATP sensitive potassium channel
| Medicine | Concentration mol.L -1＝M | Binding kinetics parameter (* 10 -2nM -1. minute -1) | Kinetic parameter dissociates | |||
| k obs | k 1 | k A | k 2(×10 2nM -1. minute -1) | K d(nM) | ||
| Control compound 1 Pinacidil ATP | 10 -4 10 -4 10 -2 10 -3 5×10 -3 10 -3 | 4.65±0.37 2.90±0.74 * 2.32±0.67 ** 7.69±1.01 ** 2.28±0.70 ** 4.26±0.65 2.83±0.35 * | 1.31±0.14 0.62±0.25 * 0.39±0.24 ** 2.42±0.34 ** 0.45±0.24 ** 1.15±0.23 0.55±0.14 * | 181.90±46.90 61.04±25.89 * 33.91±22.43 ** 590.20±208.20 ** 47.80±25.70 ** 143.50±49.00 47.40±14.70 ** | 0.72±0.11 1.02±0.14 * 1.15±0.27 * 0.42±0.14 * 0.94±0.10 * 0.80±0.22 1.17±0.21 * | 0.55±0.14 1.64±0.69 * 2.95±0.95 * 0.17±0.06 * 2.09±1.12 * 0.70±0.24 2.11±0.65 * |
Data are represented with average ± standard deviation of 4-10 experiment gained result; The test of significance of difference is adopted variance analysis and control group relatively, * p＜0.05, * * p＜0.01 between data.
Table 10 compound 1 to [
3H]-influence of P1075 and vascular smooth muscle ATP sensitive potassium channel binding kinetics
| Medicine | Concentration (mol.L -1＝M) | Binding kinetics parameter (k obs，×10 -2nM -1. minute -1) |
| Control compound 1 glibenclamide ATP ADP |
10 -4 10 -5 10 -2 10 -3 5×10 -5 10 -3 10 -3 | 4.36±0.45 2.44±0.80 * 3.12±0.17 * 2.85±0.08 * 2.63±0.48 * 5.53±0.51 * 3.86±0.19 3.07±0.24 * |
Data are represented with 4-10 experiment gained result's mean+SD; T check is in groups adopted in the test of significance of difference between data, compares * p＜0.05 with control group.
[
3H]-Glyburide and [
3H]-P1075 respectively on the thiocarbamide acceptor of label vascular unstriated muscle ATP sensitive potassium channel by the site of antagonist and agonist, as shown in table 9,10
-4M compound 1,10
-4M Pinacidil, 10
-3M ADP and 10
-3M Ade all suppress [
3H]-cohesive process of Glyburide and vascular smooth muscle ATP sensitive potassium channel, promote [
3H]-dissociation process of Glyburide and vascular smooth muscle ATP sensitive potassium channel.10
-2M ATP promotion [
3H]-cohesive process of Glyburide and vascular smooth muscle ATP sensitive potassium channel, and suppress [
3H]-dissociation process of Glyburide and vascular smooth muscle ATP sensitive potassium channel.The retarding agent binding site of 1 couple of vascular smooth muscle ATP of prompting compound sensitive potassium channel has the allosteric regulating effect, and its interaction property is similar to Pinacidil, and opposite with ATP.As shown in table 10,10
-4M compound 1,10
-5M Glyburide, 10
-2M ATP, 10
-3M ADP and 10
-3M Ade all suppress [
3H]-cohesive process of P1075 and ATP sensitive potassium channel, UDP then promote [
3H]-cohesive process of P1075 and ATP sensitive potassium channel, the agonist binding site of 1 couple of vascular smooth muscle ATP of prompting compound sensitive potassium channel also has the allosteric regulating effect, its interaction property is similar to Glyburide, ATP, ADP and Ade, but opposite with UDP.
The allosteric regulating effect of 1 couple of vascular smooth muscle ATP of dynamic experiment research compound sensitive potassium channel of radioligand and receptors bind is adopted in this experiment 4.
1. the method that selectivity retardance agent Glyburide binding site allosteric is regulated on 1 couple of vascular smooth muscle ATP of compound sensitive potassium channel is as follows: body weight 340 ± 20g, after the male Wistar rat sacrificed by decapitation, cut thoracic cavity taking-up aorta rapidly open and place 4 ℃ of buffered soln flush away bloodstain that contain the physiology salt of 10mM HEPES, the careful fat of removing, reticular tissue and thrombus on every side, aorta is cut into the arterial ring that is about 3-5mm, cut the back and wipe blood vessel endothelium with wet cotton swab, suck dry moisture, weigh, insert then in the reaction tubes of the physiology salt buffer that fills an amount of precooling.During the binding kinetics experiment, the aorta sample in the differential responses pipe is earlier respectively with 10
-4M compound 1 and 10
-4M Pinacidil, 10
-2M ATP, 10
-3M adenosine diphosphate (ADP) (ADP), 10
-3M adenosine (Ade), 5 * 10
-5M uridine diphosphate (UDP) (ADP) and etc. the damping fluid of capacity in 25 ℃ of water-baths, incubated altogether 10 minutes, all add 3nM[in each reaction tubes then
3H]-Glyburide continues to hatch: added the ice-cold 50mM Tris damping fluid of 9mL in 5,10,15,20,30,60,90 and 120 minutes respectively at hatching the back, termination reaction was also embathed 1 minute, separated free and bonded [
3H]-Glyburide, take out aorta sample, go in the scintillation vial behind the suck dry moisture, add 50 μ L30% hydrogen peroxide then successively, digest 2h in 80 ℃ after covering tight bottle stopper, the dimethylbenzene that adds 2.5mL ethylene glycol ethyl ether and 5mL1%B-BPD after the cooling successively leaves standstill behind the 8h and measures radioactivity cpm value down in liquid scintillation counter, and the gained result is with In[B
EQ/ (B
EQ-B
t)] time t is done straight-line regression, the calculations incorporated kinetic parameter.Do when dissociating dynamic experiment, through above-mentioned binding kinetics test the pretreated aorta sample of same medicine with [
3H]-Glyburide 25 ℃ incubate 60 minutes altogether after, add the Glyburide of 30 μ M, and after dosing, measured in the same way in 0,5,15,30,60,90,120 minute [
3H]-the radioactivity radioactivity cpm value of Glyburide and ATP sensitive potassium channel mixture, the gained result is with In (B/B
EQ) time t is done straight-line regression, computational solution is from kinetic parameter.
2. the method that selectively activate agent P1075 binding site allosteric is regulated on 1 couple of vascular smooth muscle ATP of research compound sensitive potassium channel is as follows: remove incubation temperature and change 37 ℃ into, change 5,10,15,20,30,45,60,90 minutes the sample time of binding kinetics process into, dissociate and change into outside 1,3,5,10,20,30,45,60 minute sample time of dynamic process, other operation just replaces corresponding Glyburide with P1075 with above-mentioned experimental technique.
Biological effect test 1 pair of 5 compound vascular smooth muscle ATP sensitive potassium channel and its highly selective activator [
3H] influence of P1075 specificity bonded
Shown in Fig.1, non-marked P1075 and [
3H] P10755nM and rat endothelium-denuded aortal smooth muscle sample hatch 90 minutes at 37 ℃, but P1075 concentration rely on ground suppress [
3H] the P1075 combination, its IC
50Value is 9.1 ± 1.3nM, and pKi is 8.04 ± 0.88.But all concentration dependence ground inhibition of Pinacidil, compound 1 and Glyburide under same experimental conditions [
3H] the specificity combination of P1075, IC
50Value is respectively 199.5 ± 43.6nM, 354.8 ± 53.7nM and 58.9 ± 4.6 μ M, and pKi is respectively 6.70 ± 0.36, and 6.45 ± 0.73 and 4.23 ± 2.34.By relatively, compound 1 to [
3H] 1075 competitive inhibitory effect than P1075 a little less than 39 times, than a little less than the Pinacidil 1.8 times, stronger 166 times than Glyburide.But the replacement of compound 1 concentration dependent [
3H] P1075 combines 1 couple of K of compound with the specificity of vascular smooth muscle thiocarbamide acceptor
ATPThe avidity and the Pinacidil of opener binding site are close.
The research method of biological effect experiment 5 adopts the Wistar rat, 350 ± 46g, take out complete section of aorta after the sacrificed by decapitation rapidly, place 4 ℃ of 5mM HEPES buffered physiological salt solutions, behind removal surrounding tissue and tiny blood vessels branch and the bloodstain, aorta is cut into about 5～7mm, the aortic annulus of weight in wet base 5～7mg, the mechanical process endothelial tube of dehematizing after weighing, adds and contains in the reaction tubes of damping fluid.
The aortal smooth muscle sample and the 5nM[that add weight in wet base 5～7mg in the differential responses pipe
3H] potassium channel blocker Glyburide, potassium channel openers Pinacidil and P1075 and the new compound 1 of P1075 and different concns, the non-specific binding pipe adds non-marked P1075 50 μ M, the total binding pipe replaces each medicine with 5mM HEPES damping fluid, each reaction replenishes damping fluid to overall 250 μ L, shake up, measure the CPM value after hatching 90 minutes in 37 ℃.
Operation steps sees document for details: Bray KM, Quast U.A specitic binding site forK+channel openers in rat aorta.J Bio Chem, 1992; 267 (17): 11689-92. Ω
Biological effect is tested the influence of 1 pair of arteria pulmonalis smooth muscle cells potassium current of 6 compounds
On the Wistar rat, observed compound 1 (1 * 10
-6M) to the influence of arterial smooth muscle cell potassium current in the acute dispersive lung (be mainly Delayed Rectifier Potassium Current and calcium activate potassium current).Behind the cell sealing-in rupture of membranes in 1-15 minute, the relaxation phenomenon of ubiquity potassium current is 100% with the potassium current of 1-3 behind the rupture of membranes minute record, potassium current decay in 3-5 minute, and the potassium current attenuation amplitude no longer further increases after 5 minutes.Attenuation amplitude is on average between 10%-14%.Shown in Fig2-3, the potassium current amplitude of 5 minutes records is 86.97 ± 3.48% (n=8) behind the rupture of membranes.Potassium current with 3 minutes records behind the cell sealing-in rupture of membranes adds compound 1 when being 100%, 4 minute, the variation of potassium current when having observed after the administration 1,3,6,11 minute respectively.In the 13 routine cells of observing, have 8 examples after administration 1-11 minute with the normal control group relatively, potassium current has enhancement (Fig.2), and is remarkable with control group comparison enhancement in the time of 1 minute in administration, p＜0.01 (Fig.3); 5 examples are reactionless to compound 1 in addition.Originally studies show that compound 1 can promote the outflow of arterial smooth muscle cell potassium ion.
The method that experiment 5 is adopted: male Wistar rat, 200-250g, sacrificed by decapitation is separated artery in the lung rapidly, and (mmol/L:NaCl 118.3, and KCl 4.7, KH to place 4 ℃ of physiological salt solutions
2PO
41.2, MgSO
41.2, NaHCO
325, CaCl
22.5 EDTA 0.026, Glucose5.0, pH 7.4) in, modified back is cut off along major axis, removes endothelium gently with wet cotton balls, and the artery bar is cut into 1mm
2Size, (mmol/L:NaCl 126, and KCl 6, MgCl to place 37 ℃ of no calcium liquid
21.2, Hepes 10, Glucose 11, pH 7.2) in, incubated temperature 30 minutes, put into low calcium (16 μ mol/L) the enzyme liquid that contains 1mg/ml collagenase I, 2mg/ml bovine serum albumin, 5mg/ml papoid, 1.25mmol/L dithiothreitol dithio then, incubated temperature 58 minutes for 37 ℃, use 2 digestion of low calcium liquid flushing again,, slowly answer calcium then to 0.6mmol/L with the level and smooth suction pipe piping and druming of the mouth of pipe with the termination enzyme.4 ℃ of refrigerators are preserved, and can be used for patch clamp experiments in 8 hours.
The cell suspension of getting several separator wells adds in the perfusion groove, leave standstill made cell attachment in 6 minutes after, (mmol/L:NaCl 150, and KCl 5.4, MgCl with tyrode's solution
22.0, CaCl
21.2 Hepes 5, Glucose 10, and pH 7.4) perfusion, speed is 2ml/ minute.The cell of choosing smooth complete, the long shuttle type of cytolemma experimentizes.Experiment is all carried out under 22-24 ℃ room temperature.
Vascular smooth muscle cell is clamped down at-70mV, give-70～+ slope of 50mV stimulates, and speed is 200mV/s, and frequency of stimulation is 0.05Hz.
Claims (14)
1, general formula I
aShown sulfonamide derivatives, its isomer, raceme or optical isomer, medicinal acid addition salt, its acid amides or its ester,
Wherein:
(1). work as R '
1Be sec.-propyl, R '
2, R '
3During for methyl, R '
4Can be sec.-propyl, normal-butyl, isobutyl-, tertiary butyl, ring third methyl, dimethylamino ethyl, allyl group, diisopropylamino ethyl; Or
(2). work as R '
1, R '
2Be methyl, R '
3-C-NH-R '
4Can be the sulfonamide derivatives shown in the following formula, its
Isomer, raceme or optical isomer,
Wherein R and R ' are C
1-5Alkyl, n are the integer of 1-8; Or
(3). work as R '
1Be phenyl, R '
2During for methyl, R '
3Can be methyl, ethyl, sec.-propyl, R '
4Can be propyl group, methoxy carbonyl methyl; Or
(4). work as R '
1Be (CH
3)
2C (NH
2)-, R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1Be (CH
3)
2C (OH)-, R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-or (CH
3)
2CH (CH
3)-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-or R '
2With R '
3Be together-(CH
2)
4-or-(CH
2)
5-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1Be (CH
3)
2C (ONO
2)-, R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-or R '
2With R '
3Be together-(CH
2)
4-or-(CH
2)
5-time, R '
4Be (CH
3)
2CH-; Or
Work as R '
1For
R '
2, R '
3Be CH
3-time, R '
4Be (CH
3)
2CH-or (CH
3)
2CH (CH
3)-; Or
Work as R '
1For
R '
2, R '
3For-(CH
2)
5-time, R '
4Be (CH
3)
2CCH (CH
3)-; Or
(5). work as R '
1Be (CH
3)
2CH-, R '
2, R '
3Be CH
3-time, R '
4Be Val-, Trp-, Ile-, Leu-, Phe-, O
2N-Arg-, Pro-, Leu-Val-, Trp-Trp-Trp-, (CH
3)
2CH-SO
2-, perhaps R '
4Be one of following group:
Or
Or
Work as R '
1Be cyclopropyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4Be Val-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3Be CH
3-time, R '
4Be Pro-; Or
Work as R '
1Be cyclohexyl, R '
2And R '
3For-CH
2-CH
2-time, R '
4For Pro-or
2, the sulfonamide derivatives of claim 1, wherein, described compound is selected from a kind of in the group that following compound forms:
N-(1-methylethyl)-2,3-dimethyl-2-butylamine;
N-(2-methyl-propyl)-2,3-dimethyl-2-butylamine;
N-encircles third methyl-2,3-dimethyl-2-butylamine;
N-allyl group-2,3-dimethyl-2-butylamine;
N-(2-(two-(1-methylethyl) amidos) ethyl)-2,3-dimethyl-2-butylamine;
N-butyl-2,3-dimethyl-2-butylamine;
N-propyl group-Alpha-Methyl amphetamine;
N-propyl group-α, the beta-dimethyl-amphetamine;
N-(3-pyridyl) formyl radical-2,3-dimethyl-2-butylamine;
N-figured silk fabrics amine acyl group-2,3-dimethyl-2-butylamine;
N-tryptamines acyl group-2,3-dimethyl-2-butylamine;
N-(N-nitro) is arginyl-2,3-dimethyl-2-butylamine;
N-amphetamine acyl group-2,3-dimethyl-2-butylamine;
The bright amine acyl group-2 of N-, 3-dimethyl-2-butylamine;
The different bright amine acyl group-2 of N-, 3-dimethyl-2-butylamine;
N-p-toluenesulfonyl-2,3-dimethyl-2-butylamine;
N-(1-methylethyl)-2,3-dimethyl-3-hydroxyl-2-butylamine.
3, N-propyl group-2,3-dimethyl-2-butylamine.
4, claim 1 or 2 sulfonamide derivatives, wherein, the salt of described medicinal sour addition is selected from hydrochloride, vitriol, phosphoric acid salt, hydrobromate; Or acetate, oxalate, lemon salt, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt or maleate.
5, claim 1 or 2 sulfonamide derivatives, wherein, described compound is N-(1-methylethyl)-2,3-dimethyl-2-butylamine tosilate.
6, a kind of preparation is as the method for the defined formula Ia aminated compounds of claim 1, and it comprises primary amine R
1' R
2' R
3' CNH
2With R
4' X is in organic solvent, through being heated to 50-300 ℃ and/or be pressurized to 0.1-20MPa reacts, wherein R
1', R
2', R
3' and R
4' according to claim 1, X is easy leavings group; It is characterized in that described primary amine R
1' R
2' R
3' CNH
2Prepare by the following method:
At first, with the same R of urea
1' R
2' R
3' the corresponding alkene of C or alcohol or the two mixture be heated to 20-200 ℃ of prepared in reaction formula R in organic acid under vitriol oil effect
1' R
2' R
3' CNHCONH
2The alkyl urea; Then, this alkyl urea of hydrolysis prepares corresponding primary amines.Wherein, described organic acid is selected from acetate, trifluoroacetic acid or methylsulfonic acid.
7, the described method of claim 6, wherein, described primary amine and R
4X has been reflected under the catalyst action and has carried out, and described catalyzer is disacidify agent and/or phase-transfer catalyst.
8, the described method of claim 7, wherein, described disacidify agent is a Lewis base, phase-transfer catalyst is ethylene glycol or polyoxyethylene glycol.
9, the described method of claim 6, wherein, described organic solvent is toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N, accelerine or N, the N-Diethyl Aniline.
10, a kind of method for preparing Ia aminated compounds as claimed in claim 1, it comprises primary amine R
1' R
2' R
3' CNH
2With R
4' corresponding aldehydes or ketones is at catalyzer and have/organic solvent-free in the presence of, through being heated to 30-300 ℃ and/or be pressurized to 0.1-20MPa and carry out hydrogenation, R wherein
1', R
2', R
3' and R
4' according to claim 1; It is characterized in that described primary amine R
1' R
2, R
3' CNH
2The preparation method as described in the claim 6.
11, the described method of claim 10, wherein, described catalyzer is palladium-charcoal, Raney's nickel, platinum oxide and nickel-copper.
12, the described method of claim 10, wherein, described organic solvent is corresponding excessive aldehydes or ketones, toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, methyl alcohol and ethanol.
13, claim 1 or 2 sulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt, its acid amides or its ester can be used for preventing or treat the application of the instrument medicine of the medicine of cardiovascular disorder, diabetes, segmental bronchus and urinary system smooth muscle spasm or, nerve cardiovascular as being used for studying and pancreatic cell potassium channel and function in preparation.
14, pharmaceutical composition, it contains sulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt of the arbitrary requirement of at least a claim 1-5, acid amides or its ester and pharmaceutical carrier or vehicle.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01101656 CN1250519C (en) | 2001-01-19 | 2001-01-19 | Amine derivative with K channel regulation function and its preparing process and application |
| KR1020097003591A KR20090028654A (en) | 2001-01-19 | 2002-01-21 | Amine derivatives modulating the funcitons of potassium channels, the preparation methods and uses thereof |
| PCT/CN2002/000029 WO2003080556A1 (en) | 2001-01-19 | 2002-01-21 | Amine derivative with potassium channel regulatory function, its preparation and use |
| JP2003578314A JP4279685B2 (en) | 2001-01-19 | 2002-01-21 | Amine derivatives that regulate the function of potassium channels, methods for their preparation and their use |
| DE60235535T DE60235535D1 (en) | 2001-01-19 | 2002-01-21 | AMINE DERIVATIVITY WITH CALIUM CHANNEL REGULATING FUNCTION, PRODUCTION AND USE THEREOF |
| KR1020037009608A KR100939243B1 (en) | 2001-01-19 | 2002-01-21 | Amine derivatives modulating the funcitons of potassium channels, the preparation methods and uses thereof |
| AU2002226266A AU2002226266A1 (en) | 2001-01-19 | 2002-01-21 | Amine derivative with potassium channel regulatory function, its preparation and use |
| US10/466,712 US7560473B2 (en) | 2001-01-19 | 2002-01-21 | Amine derivative with potassium channel regulatory function, its preparation and use |
| EP02716048A EP1386908B1 (en) | 2001-01-19 | 2002-01-21 | Amine derivative with potassium channel regulatory function, its preparation and use |
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|---|---|---|---|
| CN 01101656 CN1250519C (en) | 2001-01-19 | 2001-01-19 | Amine derivative with K channel regulation function and its preparing process and application |
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| CN112174834A (en) * | 2020-10-20 | 2021-01-05 | 江苏恩华赛德药业有限责任公司 | Eptacrine hydrochloride B crystal form and preparation method thereof |
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| TWI349666B (en) * | 2004-03-12 | 2011-10-01 | Lundbeck & Co As H | Substituted morpholine and thiomorpholine derivatives |
| CN106631823B (en) * | 2016-12-20 | 2022-04-26 | 天津泰普制药有限公司 | Preparation method of lorcaserin intermediate |
| CN115724799A (en) * | 2021-08-26 | 2023-03-03 | 杭州和正医药有限公司 | Potassium channel regulator, composition and application |
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| CN112174833A (en) * | 2020-10-20 | 2021-01-05 | 江苏恩华赛德药业有限责任公司 | Crystal form A of escargoline hydrochloride and preparation method thereof |
| CN112174834A (en) * | 2020-10-20 | 2021-01-05 | 江苏恩华赛德药业有限责任公司 | Eptacrine hydrochloride B crystal form and preparation method thereof |
| CN112174834B (en) * | 2020-10-20 | 2022-03-15 | 江苏恩华赛德药业有限责任公司 | Eptacrine hydrochloride B crystal form and preparation method thereof |
| CN112174833B (en) * | 2020-10-20 | 2022-03-15 | 江苏恩华赛德药业有限责任公司 | Crystal form A of escargoline hydrochloride and preparation method thereof |
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