CN1415596A - Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science - Google Patents
Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science Download PDFInfo
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- CN1415596A CN1415596A CN 01137272 CN01137272A CN1415596A CN 1415596 A CN1415596 A CN 1415596A CN 01137272 CN01137272 CN 01137272 CN 01137272 A CN01137272 A CN 01137272A CN 1415596 A CN1415596 A CN 1415596A
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Abstract
An amine derivative for resisting high pressure of lung artery, its isomer, racemate, optical isomer and salt for medicines, its amide or ester, the medical composition containing them, its preparing process, and its application in preparing medicines to prevent and cure anoxia, chronic bronchitis, pneumonectasis, pulmonary tuberculosis, etc are disclosed.
Description
The present invention relates to have sulfonamide derivatives, its steric isomer, its pharmaceutical salts of prevention or treatment pulmonary hypertension, its preparation method and in prevention or treatment by pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis or the application in the agnogenic primary pulmonary hypertension.
Pulmonary hypertension is the major disease of serious harm human health, and along with the continuous progress of the state of an illness, pulmonary hypertension can cause lung, cardiac insufficiency and other organ injury, and final the appearance breathes and right heart failure.Pulmonary hypertension can significantly reduce patient's work capacity, and its disability rate is very high, brings heavy economical load for family and society.
In the modern medicine field, pulmonary hypertension still is a problem of failing to solve fully.Pulmonary hypertension mostly is nonspecific to patient's influence and the clinical symptom that pulmonary hypertension showed, thereby can not cause enough attention.People lack perfect understanding for the generation evolution and the fundamental mechanism thereof of pulmonary hypertension.The pathogeny complexity of pulmonary hypertension is not illustrated at present as yet fully, and existing pathomechanism comprises: (1) left atrium blood drainage is not smooth, makes the venous pressure rising and causes the Ppa pulmonary artery pressure passivity to raise; (2) with or can cause the lung vasoconstriction without acidosic alveolar anoxic, cause Ppa pulmonary artery pressure to raise.Persistent alveolar anoxic can cause the pulmonary artery pressure long term maintenance in high level, becomes pulmonary hypertension.(3) area of section of pulmonary vascular bed dwindles, and pulmonary vascular resistance increases, and causes pulmonary hypertension.The medicine for the treatment of pulmonary hypertension clinically comprises: cardiac tonic such as digoxin, diuretic(s) such as hydrochlorothiazide, alpha receptor blocking agent phentolamine, calcium antagonist, prostacyclin, NO donor sodium nitroprusside, adenosine and antithrombotics warfarin etc.All there is defective in various degree in these medicines, as: the toxicity that has is big; The general untoward reaction that has is many; The no definite clinical efficacy that has etc.In a word, there is not ideal to have the medicine of the accepted treatment pulmonary hypertension of definite curative effect as yet.Therefore, the newtype drug of research and development anti-pulmonary hypertension has crucial meaning.
The application's general formula I
aSulfonamide derivatives and general formula I sulfonamide derivatives do not appear in the newspapers as yet in the purposes aspect prevention or the treatment pulmonary hypertension.
The objective of the invention is to seek and develop medicine, the especially prevention of new prevention or treatment pulmonary hypertension or treat by pulmonary hypertension or agnogenic primary pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis.
The inventor has now found that the formula I with good potassium road regulating effect through research extensively and profoundly
aOr the sulfonamide derivatives shown in the formula I, this compounds can be used for prevention or treatment pulmonary hypertension.Studies show that formula I
aOr the ammonia derivative shown in the formula I has the effect of anti-pulmonary hypertension.Further synthetic with studies show that the pharmaceutical salts of the derivative that the present invention is included and suitable mineral acid or organic acid formation has the effect of anti-pulmonary hypertension equally.The present invention is based on above-mentioned discovery is accomplished.
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 and can be used for preventing or treat purposes in the medicine of pulmonary hypertension in preparation,
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 pulmonary hypertension
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 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
Further aspect of the present invention relates to and is used to prevent or treats 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 of pulmonary hypertension
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 pulmonary hypertension, it comprises formula I or the formula I that the patient who suffers from pulmonary hypertension 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 in organic acid under vitriol oil effect; Then, 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 or nickel-copper etc., and described organic solvent is 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' CNHR
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.
According to the present invention, used term " pulmonary hypertension " is meant under the morbid state pulmonary hypertension or the agnogenic primary pulmonary hypertension due to for example anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis among the present invention.The compound of general formula I according to the present invention, R
1Be preferably the tertiary butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, isopentyl, cyclobutyl; Perhaps, R
1Be cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, dissident's base, isopentyl, isobutyl-, the sec.-propyl of alpha-substitution, wherein said substituting group is amino, hydroxyl, C
1-10Hydroxylamine base, C
1-6-oxyl, C
1-10Alkylacyloxy, C
6-10Aryl acyloxy, C
1-10Amide group;
R
2Or R
3Preferably be respectively hydrogen atom, C
1-12Chain alkylene or C
3-8Cyclic hydrocarbon radical;
R
4Be preferably hydrogen atom, C
1-20Saturated fatty alkyl, C
3-20Cycloalkyl, C
1-10Acyl group, C
1-10Hydroxylamine base C
1-10Alkyl, C
1-20Sulfoxide group, Amino acid residue and the micromolecule polypeptide fragment that combines thereof, β-nitroethylene base, beta-cyano vinyl, replacement carbonyl imido grpup, C
3-20Heterocyclic radical, and C
4-20Heterocyclic acyl.
The compound of general formula I according to the present invention, R
2, R
3More preferably be respectively methyl, ethyl, propyl group, perhaps, R
2And R
3Be propylidene, butylidene, pentylidene and inferior hexyl.
In a preferred embodiment of the invention, described R
1Be sec.-propyl, R
2Be methyl, R
3Be methyl.
According to the present invention, formula I
aCompound 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-propenyl-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-is valyl-2,3-dimethyl-2-butylamine;
N-tryptophyl-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-trichlorobenzene oxygen ethanoyl)-2,3-dimethyl-2-butylamine.
According to the present invention, the acid salt of formula I compound 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 and maleate; As N-(1-methylethyl)-2,3-dimethyl-2-butylamine tosilate.
The invention further relates to new being used to and prevent or treat the general formula I of pulmonary hypertension
aShown sulfonamide derivatives, its isomer, raceme or optical isomer, medicinal acid addition salt,
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 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 prevention or neural hypoxic-ischemic such as treatment brain and spinal cord damage.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, imidazolinyl, thiazolinyl, pyrazolinyl, dihydro miaow quinoline base, thiazoline quinoline base, pyrazoline quinoline base, N-substituted acyl pyrazolinyl, N-substituted acyl glyoxalidine 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 spiral shell cyclohexyl, 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.
The preferred formula I compound of table 1, in its Chinese style, each substituting group is alkyl compound R1 R
2 R
3 R
4Molecular formula 1 (CH3)
2CH- CH
3- CH
3- (CH
3)
2CH- C
9H
21N
2 (CH
3)
2CH- CH
3- CH
3- H- C
6H
15N
3 (CH
3)
2CH- CH
3- CH
3- CH
3- C
7H
17N
4 (CH
3)
2CH- CH
3- CH
3- C
2H
5- C
8H
19N
5 (CH
3)
2CH- CH
3- CH
3- CH
3CH
2CH
2- C
9H
21N
6 (CH
3)
2CH- CH
3- CH
3- n-C
4H
9- C
10H
23N
7 (CH
3)
2CH- CH
3- H- (CH
3)
2CH- C
8H
19N
8 H- H- H- (CH
3)
2CH- C
4H
11N
9 C
2H
5- CH
3- CH
3- (CH
3)
2CH- C
6H
15N
10 C
2H
5- CH
3- H- H- C
4H
11N
11 C
2H
5- CH
3- CH
3- CH
3- C
6H
15N
12 C
2H
5- CH
3- H- H- C
4H
11N
13 (CH
3)
2CH- CH
3- CH
3- (CH
3)
2CHCH
2- C
10H
23N
14 (CH
3)
2CH- CH
3- CH
3- t-C
4H
9- C
10H
23N
15 (CH
3)
2CH- CH
3- CH
3-
C
10H
21N
16 (CH
3)
2CH- CH
3- CH
3- (CH
3)
2NCH
2CH
2- C
10H
24N
2
17 Ph- CH
3- CH
3- CH
3OCOCH
2- C
12H
17NO
2
18 Ph- CH
3- C
2H
5- (CH
3)
2NCH
2CH
2- C
14H
24N
2
19 Ph- CH
3- (CH
3)
2CH- (CH
3)
2CH- C
14H
23N
20 Ph- CH
3- CH
3- CH
3CH
2CH
2- C
12H
19N
21 Ph- C
2H
5- CH
3- CH
3CH
2CH
2- C
13H
21N
22 Ph- (CH
3)
2CH- CH
3- CH
3CH
2CH
2- C
14H
23N
23 (CH
3)
2CH- CH
3- CH
3- CH
3OCOCH
2- C
9H
19NO
2
24 (CH
3)
2CH- CH
3- CH
3- PhCH
2- C
13H
21N
25 (CH
3)
2CH- CH
3- CH
3- CH
2＝CH-CH
2- C
9H
19N
26 (CH
3)
2CH- CH
3- CH
3- (CH
3)
2CH-CH
2- C
10H
23N
27 (CH
3)
2CH- CH
3- CH
3- ((CH
3)
2CH)
2NCH
2CH
2- C
14H
32N
2
28
CH
3- CH
3- (CH
3)
2CH- C
12H
25N
29
CH
3- CH
3- (CH
3)
2NCH
2CH
2- C
13H
28N
2
30
CH
3- CH
3- PhCH
2- C
16H
25N
31
CH
3- CH
3- CH
3OCOCH
2- C
12H
23NO
2
32
-CH
2-CH
2- (CH
3)
2CH- C
9H
17N
33
-CH
2-CH
2- (CH
3)
2NCH
2CH
2- C
10H
20N
2
34
-CH
2-CH
2- PhCH
2- C
13H
17N
35
-CH
2-CH
2- CH
3OCOCH
2- C
9H
15NO
2
36
CH
3- CH
3- (CH
3)
2CH- C
9H
22N
2
Work as R
1Be alkyl, cycloalkyl, α-amido alkyl or α-amide group cycloalkyl, R
2And R
3All be alkyl and alkylidene group, R
4During for amino acid acyl, small molecules peptide chain, sulfonic acid acyl group, aroyl or heterocyclic acyl, preferred formula I compound sees Table 2.
The preferred formula I amine derivative of table 2, have the acyl substituent compound R in its Chinese style1 R
2 R
3 R
4Molecular formula 37 (CH3)
2CH- CH
3- CH
3- Val- C
11H
24N
2O
38 (CH
3)
2CH- CH
3- CH
3-
C
13H
21N
2OS
39 (CH
3)
2CH- CH
3- CH
3-
C
12H
28N
2O
40 (CH
3)
2CH- CH
3- CH
3- Trp- C
17H
25N
3O
41 (CH
3)
2CH- CH
3- CH
3- Ile- C
12H
26N
2O
42 (CH
3)
2CH- CH
3- CH
3- Leu- C
12H
26N
2O
43 (CH
3)
2CH- CH
3- CH
3- Phe- C
15H
24N
2O
44 (CH
3)
2CH- CH
3- CH
3- O
2N-Arg- C
12H
26N
6O
3
45 (CH
3)
2CH- CH
3- CH
3- Pro- C
11H
22N
2O
46 (CH
3)
2CH- CH
3- CH
3- Leu-Val- C
17H
35N
3O
2
47
-CH
2-CH
2- Val- C
11H
20N
2O
48 (CH
3)
2CH- CH
3- CH
3- Trp-Trp-Trp- C
39H
45N
7O
3
49
CH
3- CH
3- Pro- C
14H
26N
2O
50
-CH
2-CH
2- Pro- C
14H
24N
2O
51 (CH
3)
2CH- CH
3- CH
3- (CH
3)
2CHSO
2- C
9H
21N
2OS
52 (CH
3)
2CH- CH
3- CH
3-
C
13H
18ClNO
53 (CH
3)
2CH- CH
3- CH
3-
C
12H
24N
2O
2
54 (CH
3)
2CH- CH
3- CH
3-
C
12H
19NOS
55 (CH
3)
2CH- CH
3- CH
3-
C
16H
22N
2O
56
-CH
2-CH
2-
C
15H
20N
2O
57
CH
3- CH
3 (CH
3)
2CH- C
16H
26ClN
2O
R
2, R
3And R
4All be that alkyl or alkylidene group replace R
1When replacing 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 compound R that alcohol or its ester are arranged in table 3 substituting group
1R
2R
3R
4Molecular formula 58
CH
3-CH
3-(CH
3)
2CH-C
9H
21NO59
CH
3-CH
3-
C
12H
27NO60
CH
3-CH
3-(CH
3)
2CH-C
12H
25NO61
-(CH
2)
5-(CH
3)
2CH-C
15H
29NO62
CH
3-CH
3-(CH
3)
2CH-C
11H
23NO63
-(CH
2)
4-(CH
3)
2CH-C
13H
25NO64
CH
3-CH
3-(CH
3)
2CH-C
9H
20N
2O
365
CH
3-CH
3-(CH
3)
2CH-C
12H
24N
2O
366
CH
3-CH
3-(CH
3)
2CH-C
11H
22N
2O
367
-(CH
2)
5-(CH
3)
2CH-C
15H
28N
2O
368
-(CH
2)
4-(CH
3)
2CH-C
13H
24N
2O
369
CH
3-CH
3-(CH
3)
2CH-C
15H
24N
2O
270
CH
3-CH
3-
C
18H
30N
2O
271
-(CH
2)
5-
C
24H
38N
2O
2
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 4 R
4Formula I compound compound R for heterocyclic substituent
1R
2R
3R
4Molecular formula 72 (CH
3)
2CH-CH
3-CH
3-
C
9H
19N
373 (CH
3)
2CH-CH
3-CH
3-
C
9H
18N
2O74 (CH
3)
2CH-CH
3-CH
3-
C
9H
18N
2S75
CH
3-CH
3-
C
12H
23N
376
CH
3-CH
3-
C
11H
21N
377
CH
3-CH
3-
C
12H
22N
2S78
CH
3-CH
3-
C
11H
20N
2S79
CH
3-CH
3-
C
12H
22N
2O80
CH
3-CH
3-
C
11H
20N
2O81 (CH
3)
2CH-CH
3-CH
3-
C
15H
22N
4O82 (CH
3)
2CH-CH
3-CH
3-
C
21H
30N
4O
283 (CH
3)
2CH-CH
3-CH
3-
C
12H
25N
384 (CH
3)
2CH-CH
3-CH
3-
C
10H
21N
3
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 with C
1-10Organic acid generates derivatives such as acid amides or ester, 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 cyclohexane, 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 alpha-amino group replace, 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, that is, earlier with the same R of urea
1R
2R
3Corresponding alkene of C or alcohol or the mixture of the two are heated to 20-200 ℃ of prepared in reaction alkyl urea R in organic acid under vitriol oil effect
1R
2R
3CNHCONH
2Wherein, 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 show excellent results in prevention or treatment pulmonary hypertension.Therefore can be used as prevention or treatment primary pulmonary hypertension or, be preferred for Mammals, particularly the people because the medicine of the pulmonary hypertension that anoxic, chronic bronchitis, bronchial asthma etc. cause is used for animal.
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 pH10 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 bp105-108 ℃/5mmHg 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 bp135-145 ℃ of fraction, productive rate 68.8%.Hydrochloride mp228-230 ℃ of (i-PrOH: Et
2O).Ultimate analysis C
9H
22ClN (%) calculated value C60.14, H12.34, N7.79, Cl19.73, measured value C60.14, H12.48, N7.31, Cl19.67.
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, mp175-176 ℃, 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 bp135-145 ℃ of fraction, productive rate 68.8%.Hydrochloride mp228-230 ℃ of (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)。
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 bp140-145 ℃ of cut, 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%, mp183-185 ℃.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%, hydrochloride mp203-204 ℃.Ultimate analysis C
10H
14NCl (%) calculated value C61.99, H1249, N7.23, measured value C62.17, H13.18, N7.27; 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%, hydrochloride mp176-178 ℃.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%, hydrochloride mp173-175 ℃.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%, hydrochloride mp176-178 ℃.Ultimate analysis C
14H
34N
2Cl
2(%) calculated value C55.8, H 11.37, and N 9.3, measured value C55.90, H11.68, N9.21.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%.Hydrochloride mp140-142 ℃, 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.Mp159-161 ℃ of preparation hydrochloride.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.Mp190-192 ℃ of preparation hydrochloride.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) methyl-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 C59.36, H7.89, N11.54, measured value C59.33, H7.98, N11.45.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-are valyl-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%, hydrochloride mp240-241 ℃ after the drying.Ultimate analysis C
11H
25ClN
2O (%) calculated value C55.80, H10.64, N11.83, example value C55.85, H10.71, N11.63; MS (m/z) 201.0 (M
+).
Embodiment 12 N-tryptophyl-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%, hydrochloride mp135-137 ℃ (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 mp175 (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.Hydrochloride mp250-252 ℃ (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.Hydrochloride mp246-248 ℃ (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, mp80-89 ℃, recrystallization in Virahol again, white crystals shape solid 0.8 gram, mp88-89 ℃.Ultimate analysis C
13H
21NO
2S (%): theoretical value C61.14, H8.29, N5.48, experimental value C61.11, H8.37, N5.55; 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 as for.Bp60-65/10mm Hg cut is collected in underpressure distillation, gets 2-(N-2-methylethyl)-3-hydroxyl-2, the 3-dimethyl butylamine.Hydrochloride mp156-158 ℃ (dehydrated alcohol/anhydrous diethyl ether).Ultimate analysis C
9H
22ClNO (%) calculated value C55.23, H11.33, N7.16, measured value C55.23, H11.65, N6.95; 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, mp119-120 ℃ 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-cyclohexane recrystallization, get colorless solid 130.5g (95.5%), mp228-230 ℃ of (i-PrOH: Et
2O).Ultimate analysis C
9H
22ClN (%) calculated value C60.14, H12.34, N7.79, Cl19.73, measured value C60.14, H12.48, N7.31, Cl19.67.
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 (thexylamine)
+, 85.1 (C
6H
13 +). following biological activity test is used for further specifying the present invention.
1 pair of endothelin-1 of biological effect EXPERIMENTAL EXAMPLE 1 formula I representative compounds of the present invention causes the influence of SD pulmonary arterial pressure in rats highly compressed
As shown in table 1, the SD rat is injected endothelin-1 1.5 μ g/kg through pulmonary artery can bring out pulmonary hypertension, and 5-30min after the administration, mean pulmonary arterial pressure (mPAP) are significantly higher than the preceding level of administration; Compare with the physiological saline group, compound 10.5 and 1.0mg/kg do not have obvious influence (P＞0.05) to normal Ppa pulmonary artery pressure.Show that 1 pair of normal Ppa pulmonary artery pressure of compound do not have influence.
1 pair of normal mean pulmonary arterial pressure of table 1. compound, (mPAP) influence before the medicine n administration different time after the administration, (min) mPAP, (mmHg), (mg/kg) 5 10 20 30 60 physiological saline group 7 20.6 ± 1.8 20.1 ± 1.6 20.3 ± 1.5 20.4 ± 1.1 20.6 ± 1.7 21.0 ± 2.1 endothelin-1 group 13 21.4 ± 2.6 26.2 ± 3.9
*26.1 ± 4.2
*25.8 ± 4.3
*24.8 ± 3.6
*22.0 ± 2.5 compound 1 0.5 7 20.9 ± 1.1 20.7 ± 1.2
##20.6 ± 2.2
##19.9 ± 1.6
##20.3 ± 1.1
##20.9 ± 1.1 compound 1 1.0 8 20.0 ± 2.4 20.0 ± 2.9
##20.4 ± 2.4
##20.0 ± 1.8
##20.4 ± 2.6
##19.6. ± 1.7
#Compare * * P＜0.01 with the physiological saline group; Compare with the endothelin-1 group,
#P＜0.05,
##P＜0.01.
As shown in table 2, the SD rat is injected compound 10.5 or 1.0mg/kg earlier through pulmonary artery, injects 1.5 μ g/kg endothelin-1s then, observes medicine causes pulmonary hypertension to endothelin-1 prophylactic effect.The pulmonary hypertension that compound 10.5 and 1.0mg/kg can prevent endothelin-1 to bring out approaches the level of physiological saline group all significantly being lower than the endothelin-1 group with 5,10,15,30 and 60 minutes mPAP behind the compound 11.0mg/kg; Compound 10.5mg/kg is only to 7,8, and 9,15,25 and 35 minutes Ppa pulmonary artery pressures increase prophylactic effect.Prompting compound 1 has the effect of the pulmonary hypertension that significant anti-endothelin-1 causes.
1 pair of endothelin-1 of table 2. compound, (ET) cause before the prophylactic effect medicine n administration of pulmonary hypertension different time after the administration, (min) mPAP, (mmHg), (mg/kg) 5 10 20 30 60 physiological saline group 7 20.6 ± 1.8 20.1 ± 1.6 20.3 ± 1.5 20.4 ± 1.1 20.6 ± 1.7 21.0 ± 2.1 endothelin-1 group 13 21.4 ± 2.6 26.2 ± 3.9
*26.1 ± 4.2
*25.8 ± 4.3
*24.8 ± 3.6
*22.0 ± 2.5 compounds 1 0.5+ET 7 18.0 ± 2.6 20.8 ± 5.3 20.1 ± 4.2 20.1 ± 4.3 19.5 ± 3.3 19.3 ± 2.3 compounds, 1 1.0+ET 7 19.1 ± 1.5 20.9 ± 2.4
##21.2 ± 2.3
##20.6 ± 2.6
##19.9 ± 1.7
##18.7 ± 1.5
##Compare * * P＜0.01 with the physiological saline group; Compare with the endothelin-1 group,
#P＜0.05,
##P＜0.01.
As shown in table 3, the SD rat is injected 1.5 μ g/kg endothelin-1s earlier through pulmonary artery, injects compound 10.5 or 1.0mg/kg then, observes medicine causes pulmonary hypertension to endothelin-1 therapeutic action.Compound 10.5 and 1.0mg/kg are relatively poor to the pulmonary hypertension therapeutic action that endothelin-1 brings out.
1 pair of endothelin-1 of table 3. compound, (ET) cause before the therapeutic action medicine n administration of pulmonary hypertension different time after the administration, (min) mPAP, (mmHg), (mg/kg) 5 10 20 30 60 physiological saline group 7 20.6 ± 1.8 20.1 ± 1.6 20.3 ± 1.5 20.4 ± 1.1 20.6 ± 1.7 21.0 ± 2.1 endothelin-1 group 13 21.4 ± 2.6 26.2 ± 3.9
*26.1 ± 4.2
*25.8 ± 4.3
*24.8 ± 3.6
*22.0 ± 2.5ET+ compound 1 0.5 7 22.4 ± 1.4 24.3 ± 4.4
*24.3 ± 3.8
*25.7 ± 4.7
*25.3 ± 4.2
*23.4 ± 3.4ET+ compound 1 1.0 7 22.0 ± 2.1 23.4 ± 2.7
*22.1 ± 2.0 21.7 ± 1.5 22.3 ± 1.8 22.3 ± 1.2 with the physiological saline group relatively, * P＜0.05, * * P＜0.01.
Above biological effect EXPERIMENTAL EXAMPLE 1 prompting: inject endothelin-1 through pulmonary artery and can bring out pulmonary hypertension, compound 10.5 and 1.0mg/kg do not have obvious influence to normal Ppa pulmonary artery pressure, but the pulmonary hypertension that can prevent endothelin-1 to bring out, and the pulmonary hypertension therapeutic action that endothelin-1 is brought out is relatively poor.
The research method of biological effect EXPERIMENTAL EXAMPLE 1: SD rat 280-320g, ♂.Anaesthetize through 20% urethane intraperitoneal injection, the microtubular that inserts full heparin solution through the right side external jugular vein reaches pulmonary artery, connect pressure transducer, with four road physiograph record rat mean pulmonary arterial pressures (mPAP), the while recorded heart rate, and, stablize and measure the basic hemodynamic index of record after 30 minutes by femoral artery record body circulation pressure.Inject compound 10.5 and 1.0mg/kg through pulmonary artery, observing medicine influences normal mean pulmonary arterial pressure (mPAP); Inject compound 10.5 or 1.0mg/kg earlier through pulmonary artery, inject 1.5 μ g/kg endothelin-1s then, observe medicine causes pulmonary hypertension to endothelin-1 prophylactic effect; Inject 1.5 μ g/kg endothelin-1s earlier through pulmonary artery, inject compound 10.5 and 1.0mg/kg then, observe medicine causes pulmonary hypertension to endothelin-1 therapeutic action.
Experimental technique sees reference for details: Guan Zhanjun etc.The relation of Chronic Hypoxic Rats pulmonary hypertension and hypertrophy of right heart and DOPAMINE CONTENT IN RABBIT.Chinese Medical Journal 1990; 70 (10): 582
The influence of the aorta contraction that 1 pair of endothelin-1 of biological effect EXPERIMENTAL EXAMPLE 2 formula I representative compounds of the present invention causes
As shown in Figure 1, in the calcic nutritive medium, compound 10.5-100 μ mol/L can partly resist the blood vessel function that contracts of endothelin-1, and the maximum diastolic rate of compound 1100 μ mol/L is 65.4 ± 14.6% (n=6), the EC of its vasodilator effect
50± L
95Be 5.5 ± 4.0 μ mol/L, b ± S
bBe 0.29 ± 0.05, r=0.94 (P＜0.05).In no calcium nutritive medium, compound 10.5-100 μ mol/L antagonism endothelin-1 contracts vasoactive effect than obviously weakening in the calcic nutritive medium, and the maximum diastolic rate of compound 1100 μ mol/L only is 36.4 ± 11.0% (n=6).Prompting compound 1 antagonism endothelin-1 contract flow in blood vessel function and its prevention extracellular Ca2 relevant.
The research method of biological effect EXPERIMENTAL EXAMPLE 2: with the male Wistar rat sacrificed by decapitation, open chest taking-up thoracic aorta rapidly and fall branch, place cold (4 ℃) vascular nutrition liquid, the composition of nutritive medium (mmol/L): NaCl 117, and KCl 5, CaCl
21.5, NaH
2PO
41.0, NaHCO
325, MgSO
47H
2O 1.2, and glucose 11.5 is with distilled water preparation, pH7.4.Carefully peel off blood vessel fatty tissue on every side, the flush away clot is cut into the long vascular circle of 3mm, hangs in the bath that the 10ml nutritive medium is housed, and passes to 95%O
2And CO
25% gas mixture, vascular circle one end is fixed, and the other end is connected in tonotransducer, by the tension variation of self-balancing recorder record blood vessel.Resting tension 0.5g, 37 ℃ of constant temperature.Sample is beginning administration behind the balance 45min (every 10min changes one time of nutrition liquid) under certain tension force.(the former forms the same, the CaCl during the latter will form with no calcium nutritive medium at calcic respectively earlier
2Change 5mmol/L EGTA into) in 1nmol/L endothelin-1 preshrinking aortic annulus, observe the vasodilator effect of compound 10.5～100 μ mol/L then.
Experimental technique sees reference for details: what is magnificent, Wang Hai, Xiao Wenbin.Pinacidil and nifedipine are to the endothelin vasoactive influence of contracting.Chinese Pharmacological circular 1997; 13 (6): 502-505.
The influence of pulmonary hypertension and right ventricle reconstruct due to 1 pair of chronic hypoxia of biological effect EXPERIMENTAL EXAMPLE 3 formula I representative compounds of the present invention
As shown in table 4, chronic hypoxia can make SD rat mean pulmonary arterial pressure (MPAP) significantly increase, and right ventricle weight (RV) enlarges markedly with the ratio of left ventricle and interventricular septum weight sum (LV+S), compares P＜0.01 with normal group.Show that chronic hypoxia can make Ppa pulmonary artery pressure increase, right ventricle generation reconstruct.Preceding 30 minutes of treatment group rat anoxic every day gives compound 10.75mg/kg or 1.5mg/kg by irritating stomach, and the MPAP that can obviously suppress due to the hypoxemia raises, and makes it to maintain normal level.But 1 couple of RV/ of compound (LV+S) does not have obviously influence.
Above biological effect EXPERIMENTAL EXAMPLE 3 promptings: the property anoxic can make Ppa pulmonary artery pressure increase, right ventricle generation reconstruct.Preceding 30 minutes of anoxic is irritated stomach and is given the MPAP that SD rat compound 10.75mg/kg or 1.5mg/kg can obviously suppress due to the hypoxemia and raise, but reconstruct does not have obvious influence to right ventricle.1 pair of chronic hypoxia of table 4. compound causes prophylactic effect medicine (mg/kg) n MPAP (mmHg) RV/ (LV+S) normal group 7 20.29 ± 0.76 0.26 ± 0.06 chronic hypoxia group 7 44.29 ± 7.61** 0.39 ± 0.07** compound 1 0.75 9 20.24 ± 2.40 of pulmonary hypertension
##0.37 ± 0.07** compound 1 1.5 7 20.57 ± 1.90
##0.38 ± 0.07** and normal group are relatively, * * P＜0.01; Compare with the chronic hypoxia group,
##P＜0.01.
The research method of biological effect EXPERIMENTAL EXAMPLE 3: 30 of male SD rats, purchase in the school Experimental Animal Center, 2～3 months ages of mouse, body weight 200～220g, sub-cage rearing is freely drunk water.Be divided into 4 groups at random: 7 of normal control groups; 7 of hypoxia model groups; 0.75mg/kg 9 of treatment groups (hypoxemia+compound 1); 1.5mg/kg 7 of treatment groups (hypoxemia+compound 1).Preceding 30 minutes of treatment group anoxic every day gives compound 10.75mg/kg or 1.5mg/kg by irritating stomach.Hypoxemia is respectively organized rat to be positioned in the normal pressure low oxygen cabin, when hypoxemia begins, elder generation's nitrogen injection in the cabin, reduce oxygen concentration in the cabin, with oxygen measuring instrument and magnetic valve feedback assembly, make that oxygen concn is stable at 10 ± 0.5% in the cabin, the hypoxemia cabin has aperture to communicate with ambient atmosphere, cabin atmosphere is pressed with the external world be consistent.CO in the cabin
2With water vapour respectively with sodica calx and anhydrous chlorides of rase calcium absorption.Carry out intermittent hypoxia, 6 hours every days, 6 days weekly, the 7th day not anoxic, totally 4 weeks.The induced lung haemodynamics detects: rat is anaesthetized with 20% urethane intraperitoneal.With microguide through the external jugular vein intubate to pulmonary artery, adopt four road physiographs (RM-6200C, Chengdu Instruement Factory) records mean pulmonary arterial pressure (mPAP) and heart rate.Ventricular weight is measured: deep cutting chest after above mensuration, taking out rat heart places 10% neutral formalin solution to fix for 1 week, cut off atrial tissue, separate right ventricle (RV) and left ventricle+interventricular septum (LV+S), with the weight of dividing another name RV and LV+S behind the filter paper suck dry moisture, calculate the variation of RV/ (LV+S) reflection right ventricle weight then, to determine to have or not the right ventricle plumpness.
Experimental technique sees reference for details: Guan Zhanjun etc.The relation of Chronic Hypoxic Rats pulmonary hypertension and hypertrophy of right heart and DOPAMINE CONTENT IN RABBIT.Chinese Medical Journal 1990; 70 (10): 582.
Description of drawings:
The effect of the isolated rat aorta vessel that Fig. 1 causes for 1 pair of endothelin-1 of compound
Claims (21)
1, prevention or treatment are by the pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis or the general formula I of agnogenic primary pulmonary hypertension
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 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
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-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-propenyl-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-is valyl-2,3-dimethyl-2-butylamine;
N-tryptophyl-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-trichlorobenzene oxygen ethanoyl)-2,3-dimethyl-2-butylamine.
3, the sulfonamide derivatives of claim 1, 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.
4, the sulfonamide derivatives of claim 1, wherein, described compound is N-(1-methylethyl)-2,3-dimethyl-2-butylamine tosilate.
5, a kind of preparation is as the defined formula I of claim 1
aThe method of aminated compounds, it comprises 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' 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.
6, the described method of claim 5, wherein, described primary amine and R
4' X has been reflected under the catalyst action and carried out, described catalyzer is disacidify agent and/or phase-transfer catalyst.
7, the described method of claim 6, wherein, described disacidify agent is a Lewis base, phase-transfer catalyst is ethylene glycol or polyoxyethylene glycol.
8, the described method of claim 5, 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.
9, a kind of preparation I as claimed in claim 1
aThe method of aminated compounds, 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 2.
10, the described method of claim 9, wherein, described catalyzer is palladium-carbon, Raney's nickel, platinum oxide or nickel-copper etc.
11, the described method of claim 9, wherein, described organic solvent is corresponding excessive aldehydes or ketones, toluene, dimethylbenzene, 1,2-ethylene dichloride, 1,4-dioxane, glycol dimethyl ether, methyl alcohol or ethanol.
12, 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 treating by the application in the medicine of pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis or agnogenic primary pulmonary hypertension in preparation
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.
13, as the application of claim 12, wherein:
Described R
1Be the tertiary butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, isopentyl, cyclobutyl; Perhaps, R
1Be cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, isohexyl, isopentyl, isobutyl-, the sec.-propyl of alpha-substitution, wherein said substituting group is amino, hydroxyl, C
1-10Hydroxylamine base, C
1-6-oxyl, C
1-10Alkylacyloxy, C
6-10Aryl acyloxy, C
1-10Amide group;
Described R
2Or R
3Be respectively hydrogen atom, C
1-12Chain alkylene or C
3-20Cyclic hydrocarbon radical;
R
4Be hydrogen atom, C
1-20Saturated fatty alkyl, C
3-20Cycloalkyl, C
1-20Acyl group, C
1-10Hydroxylamine base C
1-10Alkyl, C
1-20Sulfoxide group, amino-acid residue and the micromolecule polypeptide fragment that combines thereof, β-nitroethylene base, beta-cyano vinyl, replacement carbonyl imido grpup, C
3-20Heterocyclic radical, and C
4-20The heterocyclic acyl substituting group.
14, the application of claim 12, wherein, described R
2, R
3Be respectively methyl, ethyl, propyl group, perhaps, R
2And R
3Be propylidene, butylidene, pentylidene and hexylidene.
15, claim 12 or 13 application, wherein, described R
1Be sec.-propyl, R
2Be methyl, R
3Be methyl.
16, as the application of claim 12, 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-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-propenyl-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-is valyl-2,3-dimethyl-2-butylamine;
N-tryptophyl-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-trichlorobenzene oxygen ethanoyl)-2,3-dimethyl-2-butylamine.
17, as the application of claim 12, 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.
18, as the application of claim 16, wherein, described compound is N-(1-methylethyl)-2,3-dimethyl-2-butylamine tosilate.
19, as the application of claim 12, wherein, described application is meant in medicine, the especially prevention of preparation prevention or treatment pulmonary hypertension or treats by the application in the medicine of pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis or agnogenic primary pulmonary hypertension.
20, be used to prevent or treat the medicine of pulmonary hypertension, especially the prevention or the treatment by pulmonary hypertension due to anoxic, chronic bronchitis, obstructive emphysema, bronchiectasis, bronchial asthma, pulmonary tuberculosis, pneumoconiosis, pulmonary fibrosis, multiple pulmonary microembolization and the lung arteriolitis or agnogenic primary pulmonary hypertension general formula I shown in sulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt, its acid amides or its ester
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.
21, pharmaceutical composition, it contains the formula I arbitrary requirement of at least a claim 1-4 or that claim 20 requires
aOr formula I sulfonamide derivatives, its isomer, raceme or optical isomer, its medicinal acid addition salt, acid amides or its ester and pharmaceutical carrier or vehicle.
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|---|---|---|---|
| CN 01137272 CN1205175C (en) | 2001-11-02 | 2001-11-02 | Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01137272 CN1205175C (en) | 2001-11-02 | 2001-11-02 | Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science |
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| CN1205175C CN1205175C (en) | 2005-06-08 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7794965B2 (en) | 2002-03-13 | 2010-09-14 | Signum Biosciences, Inc. | Method of identifying modulators of PP2A methylase |
| US7923041B2 (en) | 2005-02-03 | 2011-04-12 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
| CN102276698A (en) * | 2010-06-10 | 2011-12-14 | 中国人民解放军军事医学科学院毒物药物研究所 | MC4-R cyclopeptide agonist and application thereof |
| US8221804B2 (en) | 2005-02-03 | 2012-07-17 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
| US9486441B2 (en) | 2008-04-21 | 2016-11-08 | Signum Biosciences, Inc. | Compounds, compositions and methods for making the same |
| CN107436333A (en) * | 2017-09-05 | 2017-12-05 | 中国医学科学院阜外医院 | Spermine is as application of the mark in the diagnostic products of pulmonary hypertension are prepared and medicine equipment |
-
2001
- 2001-11-02 CN CN 01137272 patent/CN1205175C/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7794965B2 (en) | 2002-03-13 | 2010-09-14 | Signum Biosciences, Inc. | Method of identifying modulators of PP2A methylase |
| US7923041B2 (en) | 2005-02-03 | 2011-04-12 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
| US8221804B2 (en) | 2005-02-03 | 2012-07-17 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
| US9486441B2 (en) | 2008-04-21 | 2016-11-08 | Signum Biosciences, Inc. | Compounds, compositions and methods for making the same |
| US10583119B2 (en) | 2008-04-21 | 2020-03-10 | Signum Biosciences, Inc. | Compounds, compositions and methods for making the same |
| CN102276698A (en) * | 2010-06-10 | 2011-12-14 | 中国人民解放军军事医学科学院毒物药物研究所 | MC4-R cyclopeptide agonist and application thereof |
| CN102276698B (en) * | 2010-06-10 | 2014-02-26 | 中国人民解放军军事医学科学院毒物药物研究所 | MC4-R cyclopeptide agonist and application thereof |
| CN107436333A (en) * | 2017-09-05 | 2017-12-05 | 中国医学科学院阜外医院 | Spermine is as application of the mark in the diagnostic products of pulmonary hypertension are prepared and medicine equipment |
| CN107436333B (en) * | 2017-09-05 | 2019-12-20 | 中国医学科学院阜外医院 | Application of spermine as marker in preparation of pulmonary hypertension diagnosis product and medical instrument |
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| Publication number | Publication date |
|---|---|
| CN1205175C (en) | 2005-06-08 |
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