CN1274691C - Two new compounds for treating impotence - Google Patents
Two new compounds for treating impotence Download PDFInfo
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- CN1274691C CN1274691C CN 03100488 CN03100488A CN1274691C CN 1274691 C CN1274691 C CN 1274691C CN 03100488 CN03100488 CN 03100488 CN 03100488 A CN03100488 A CN 03100488A CN 1274691 C CN1274691 C CN 1274691C
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Abstract
The present invention belongs to the technical field of medicine, which relates to two new compounds (I' and II') for treating impotence. The two compounds are two new compounds with different structures, having the characteristics of obvious effect, long acting time and low toxicity on various sexual disorders and developed on the basis of a previous patents (Chinese patent application number is 02100198.7).
Description
Invention field:
The present invention relates to the new compound of two kinds of treatment impotence, particularly, the present invention relates to new compound of two kinds of treatment impotence and its production and use.
Background technology:
Virga (Sildenafil) is a kind of selective PDE enzyme inhibitors, its chemical name is: 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] compound of pyrimidin-7-ones, the purposes that this compound and preparation method thereof and this compound are used for the treatment of cardiovascular disorder is disclosed among the patent disclosure specification sheets CN1057464A; The purposes that this compound is used to prepare treatment buck erectile dysfunction medicine is disclosed among the CN1124926A; A kind of novel method for preparing Virga is disclosed among the CN168376A; The novel method of another kind of preparation Virga is disclosed among the CN1246478A.Although Virga has good effect to the treatment of male erectile disorder, this compound has bigger toxic side effect.
The inventor once provided a kind of new compound for the treatment of impotence (Chinese patent application number 02100198.7), and the present invention is two kinds of new compounds that continue to provide the treatment impotence on preceding patent basis.
Summary of the invention:
The purpose of this invention is to provide two kinds of new selective PDE enzyme inhibitorss, i.e. Xia Mian general formula (I) compound and pharmacologically acceptable salt thereof or its configurational isomer, this compounds has the structural formula of following general formula (I):
Wherein R1 and R2 can be identical or different, can be respectively the C1-6 alkyl, preferable methyl, and most preferably R1 and R1 all are in the cis position of piperazine ring, and all are methyl; R3 is a fatty acyl group, preferred ethanoyl; It is 2 * alkyl that the another kind of R3 is selected, preferred 2 * methyl;
Another object of the present invention has provided the method for a kind of preparation formula (I) compound;
Relate to new midbody compound in the synthetic route of The compounds of this invention, therefore, another object of the present invention has provided the midbody compound of preparation formula (I) compound;
Another object of the present invention has provided a kind of pharmaceutical composition that contains formula (I) compound as activeconstituents;
Another object of the present invention has provided the purposes that a kind of formula (I) compound is used to prepare the medicine for the treatment of the impotence disease.
On the piperazine ring of formula of the present invention (I) compound three substituent R 1, R2 and R3 are arranged, there are two not to becoming carbon atom, and R1 and R2 can be in the cis of piperazine ring or trans, therefore, there are various configurational isomers in formula (I) compound, and these isomer and pharmacologically acceptable salt thereof all belong to the scope of The compounds of this invention.A compound R 3 is a fatty acyl group, preferred ethanoyl; Another compound R 3 is 2 * alkyl, preferred 2 * methyl.R3 is the scope that fatty acyl group or 2 * alkyl all belong to The compounds of this invention.
The preferred compound of the present invention is formula (I) compound that R1 and R2 are in cis, most preferred of the present invention is that R1 and R2 are methyl and are in cis, the compound of the preferred ethanoyl of R3 or 2 * methyl, its chemical name is: 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones also, both Xia Mian formula (I ') compound; Another compound chemistry title is: 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1,1-dimethyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones also, i.e. following formula (I ") compound.
The compound of formula of the present invention (I) has good effect not only to the impotence treatment of diseases as the treatment to male erectile disorder, but also has the long and low characteristics of toxicity of duration of efficacy.
(I ") compound is the preparation method of example formula (I) compound with formula (I ') and formula below.
Formula of the present invention (I ') and formula (synthetic route of I ") compound is as follows:
(preparation of I ") compound is to be raw material with the 2-ethoxybenzoic acid, obtains 5-chlorosulfonyl-2-ethoxybenzoic acid (Compound I I) with the chlorsulfonic acid reaction in the presence of thionyl chloride for formula (I ') and formula; With compound (II) and cis-2, (its preparation method was referring to " Chinese Journal of Pharmaceuticals ",, 28 (11) in 1997 for the 6-lupetazin, the 524-525 page or leaf) reaction obtains 2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenylformic acid (compound III); The isoxazolecarboxylic acidization of compound (III) is obtained 2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) Benzoyl chloride (compound IV), and this compound is a new compound; Prepared in reaction obtains 4-[2-oxyethyl group-5-(cis-2 in the presence of 4-Dimethylamino pyridine and triethylamine with compound (V) (preparation of this compound is synthetic referring to the formula among the CN1246478A (IX) compound) with compound (IV), 6-lupetazin-4-alkylsulfonyl) benzoylamino]-1-methyl-3-n-propyl pyrazoles-5-methane amide (compound VI), this compound is a new compound; Compound (VI) cyclization under the potassium tert.-butoxide effect obtains 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (compound VI I) also.Compound (VII) selectively acylating under the acetylation reagent effect obtains 5-[2-oxyethyl group-5-(cis-2; 6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7; the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (I ') also.Compound (VII) obtains 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1,1-dimethyl-4-alkylsulfonyl) phenyl under the methylating reagent effect]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (I ") also.
Further specify formula of the present invention (I ') and the formula (preparation of I ") compound and pharmacologically acceptable salt thereof below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
Embodiment:
The preparation of embodiment 1:5-chlorosulfonyl-2-ethoxybenzoic acid (II)
In the three-necked bottle of 250ml, stir down, 2-ethoxybenzoic acid 50g (0.30mol) is splashed in the mixture of ice bath refrigerative 22ml (0.30mol) thionyl chloride and 82.6ml (1.24mol) chlorsulfonic acid, keep the temperature of reaction mixture to be lower than 25 ℃ simultaneously, with the mixture stirring at room that obtains after 18 hours, pour in the frozen water under stirring, white precipitate occurs.Continue to stir after 1 hour, filter, washing, vacuum-drying gets white solid compound (II) crude product 64.4g (yield 81%), fusing point: 108-110 ℃.Crude product does not need purifying, directly drops into the next step.
The preparation of embodiment 2:2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenylformic acid (III)
In the 250ml three-necked bottle, stir down, with 52.6g (0.23mol) cis-2, the 6-lupetazin is added in water (170ml) suspension of 53.0g (0.2mol) compound (II) under about 10 ℃, keeps reaction mixture temperature to be lower than 20 ℃ simultaneously.Finish, continue to stir 2 hours, separate out precipitation, filter in 10 ℃, the frozen water washing, drying, acetone refluxed 1 hour, and purifying obtains white crystalline compound (III) 48.0g (yield 70%), fusing point: 260.5-273.0 ℃ (decomposition).HNMR (DMSO) δ: 7.72-7.75 (2H, 4-H on the phenyl ring, 6-H), (7.26 1H, 3-H on the phenyl ring), 4.12-4.17 (2H,-OCH2-), and 3.5-3.53 (2H, piperazine ring-CH2-), 2.89-2.92 (2H, on the piperazine ring two-CH-), 1.80-1.86 (2H, on the piperazine ring-CH2-), 1.31-1.34 (3H, on the oxyethyl group-CH3), 1.0-1.04 (6H, two methyl substituents on the piperazine ring-CH3).
The preparation of embodiment 3:2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) Benzoyl chloride (IV)
The mixture of 34.2g (0.1mol) compound (III) with thionyl chloride 73.0ml (0.5mol) placed in the 250ml three-necked bottle, reflux 3 hours, remove sulfur oxychloride under reduced pressure to most, residuum adds ethyl acetate and stirs, separate out sedimentation and filtration, ethyl acetate washing, vacuum-drying, get yellow solid compound (IV) 29.4g, yield 74%.Fusing point: 206.0-209.5 ℃.HNMR (D2O) δ: 8.0 (1H, phenyl ring 6-H), 7.74-7.76 (1H, phenyl ring 4-H), 7.14-7.16 (1H, 3-H on the phenyl ring), 4.08-4.11 (2H ,-OCH2-), 3.74-3.77 (2H, on the piperazine ring-CH2-), 3.32 (2H, on the piperazine ring two-CH-), 2.19-2.25 (2H, another on the piperazine ring-CH2-), 1.24-1.27 (3H, on the oxyethyl group-CH3), 1.09-1.10 (6H, two methyl substituents on the piperazine ring-CH3).
Embodiment 4:4-[2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) benzoylamino]-preparation of 1-methyl-3-n-propyl pyrazoles-5-methane amide (VI)
In the 500ml three-necked bottle, add methylene dichloride 125ml successively, 1-methyl-4-amino-3-propyl group pyrazoles-5-benzamide compound (V) 9.1g (0.05mol), 4-Dimethylamino pyridine 0.06g (0.0005mol) and triethylamine (10.1g, 0.1mol), be cooled to below 10 ℃ with ice bath, in this solution, drip the dichloromethane solution (125ml) of 25.80g (0.065mol) compound (IV), finish, insulated and stirred 2 hours, solvent evaporated, resistates adds the water stirring and separates out solid, filters the ethyl acetate washing, dry pale solid compound (VI) 19.2g, the yield 76% of getting.Fusing point: 197-198.5 ℃.HNMR (CDCL3) δ: 8.62 (1H, the 6-H on the phenyl ring), 7.90-7.92 (1H, 4-H on the phenyl ring), 7.90 (1H ,-CO-NH-), (7.17-7.27 1H, 3-H on the phenyl ring), 5.73 (1H, on the piperazine ring-NH-), 4.37-4.41 (2H ,-OCH2-), (4.06 3H, N-CH3 on the pyrazoles ring), 3.63-3.66 (2H, on the piperazine ring-CH2-), 3.0 (2H, on the piperazine ring two-CH-), 2.52-2.56 (2H, substituted propyl 1 on the pyrazoles ring ' position-CH2-, and 1.84-1.90 (2H, another on the piperazine ring-CH2-), 1.65-1.69 (2H, substituted propyl 2 on the pyrazoles ring ' position-CH2-), and 1.58-1.63 (3H, on the phenyl ring replacement oxyethyl group-CH3), 1.03-1.05 (6H, two methyl substituents on the piperazine ring-CH3), 0.94-0.97 (3H, on the substituted propyl on the pyrazoles ring-CH3).
Embodiment 5:5-[2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is the preparation of [4,3-d] pyrimidin-7-ones (VII) also
In the 250ml three-necked bottle, add potassium metal 1.8g (0.046mol), exsiccant trimethyl carbinol 96ml adds 19g (0.038mol) compound (VI) again in this solution, and mixture is stirred, reflux 8 hours.After being cooled to room temperature, add water 96ml dilution, regulate PH=7, separate out precipitation, placed 1 hour below 10 ℃ with 0.5mol/L hydrochloric acid.Filter, the frozen water washing, drying obtains white crystalline compound (I ') 17.0g (93%).Fusing point: 202.2-203.2 ℃.HNMR (MeOD) δ: 8.15 (1H, the 6-H on the phenyl ring), 7.90-7.93 (1H, 4-H on the phenyl ring), 7.36-7.38 (1H, the 3-H on the phenyl ring), 4.32 (2H,-OCH2-), 4.23 (3H, N-CH3 on the pyrazoles ring), 3.75-3.78 (2H, on the piperazine ring-CH2-), 3.10 (2H, on the piperazine ring two-CH-), 2.86-2.89 (2H, substituted propyl 1 on the pyrazoles ring ' position-CH2-), and 2.04-2.10 (2H, another on the piperazine ring-CH2-), 1.80-1.84 (2H, substituted propyl 2 on the pyrazoles ring ' position-CH2-), and 1.45-1.48 (3H, on the oxyethyl group-CH3), 1.14-1.17 (6H, two substituent methyls on the piperazine ring-CH3), 0.97-1.01 (3H, on the substituted propyl on the pyrazoles ring-CH3).
Embodiment 6:5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is the preparation of [4,3-d] pyrimidin-7-ones (I ') also
In the 100ml flask, add the VII of 6g (0.0123mol), add 50ml methylene dichloride low-grade fever and make the VII dissolving, add the diacetyl oxide (98.5%) of 2ml (0.021mol), drip the 1.5ml pyridine again.40 ℃ of stirring reactions of water-bath 6 hours.Fling to and make an appointment with half methylene dichloride, have solid to separate out, cooling, suction filtration goes out acetylate, methanol wash.Well-established law reclaims product from mother liquor.Merge white crystals product (I ') 4.3g.HNMR (CDCL3) δ: 1.03 (3H, methyl in the n-propyl), 1.84 (2H; in the n-propyl-CH2-), 2.94 (2H, in the n-propyl-CH2-); 1.42 (6H, cis 2 * CH3) on the piperazine ring, 1.65 and 4.38 (3H and 2H; ethyl in the oxyethyl group); (2.08 3H, ethanoyl), 2.51 and 3.65 (each 2H; on the piperazine ring-CH2-); (4.28 3H, N-methyl), 4.04 and 4.70 (each 1H; piperazine ring-CH-); 7.17,7.85 and 8.82 (each 1H, three hydrogen on the phenyl ring); 10.83 (1H, on the pyrimidone ring-NH-).
Embodiment 7:5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1,1-dimethyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, also [4, the 3-d] pyrimidin-7-ones (preparation of I ") of 6-dihydro-1 h-pyrazole
In the 50ml flask, the VII that adds 0.5g (0.001ml), the yellow soda ash of 0.21g (0.0025mol) and 4g water are at 18-22 ℃ of methyl-sulfate that drips 0.315g (0.0025mol), 20-25 ℃ of following stirring reaction 1 hour, be warming up to 60-65 ℃ of reaction 1 hour rapidly, add water 10ml, 10ml again adds methylene chloride, there is solid to separate out, suction filtration, washing, the dry white solid 0.2g that gets.HNMR (DMSO-d6) δ: 0.94 (3H, in the n-propyl-CH3), 1.75 (2H, in the n-propyl-CH2-), 2.79 (2H, in the n-propyl-CH2-), 1.35 (9H, on the piperazine ring in cis dimethyl and the oxyethyl group-CH3), (2.65 3H, N-methyl), 3.09 (3H, N-methyl), (4.17 3H, pyrazoles ring N-methyl), 4.23 (2H, in the oxyethyl group-CH2-), 2.81 with 3.81 (2H and 4H, piperazine ring hydrogen), 7.40,7.91 with 7.96 (each 1H, phenyl ring hydrogen), 12.0 (on the pyrimidone ring-NH-).
The inventor discovers that compound of the present invention has good effect to the treatment of male erectile disorder, and toxic side effect is very little, and concrete pharmacodynamics and toxicity test result are summarized as follows:
One. pharmacodynamics test:
Test 1. formulas (I ') compound to extracing the establishing-Yang test of testis rat:
Test-results shows, formula (I ') compound is when dosage is 24mg/Kg and 12mg/Kg, can shorten the latent period (P＜0.05 and P＜0.01) of electricity irritation (10 volts) rat erection significantly, control compound Virga compound has identical effect (P＜0.01).
Test 2. formulas (I ') compound to extracing the influence of testis mouse sexual function:
A as a result: test-results shows that formula (I ') compound can shorten male mouse significantly and pounce on the latent period (P＜0.05 and P＜0.01) of catching female mouse when dosage is 24mg/Kg and 12mg/Kg.
B as a result: test-results shows, formula (I ') compound can obviously increase male mice female mice climbed back of the body number of times (sexual intercourse number of times) (P＜0.05 and P＜0.01) when dosage is 24mg/Kg and 12mg/Kg.
Two. toxicity test:
Use the Bliss method, the medium lethal dose LD50 that records the administration of formula (I ') compound mice lavage is 901.5mg/Kg, and 95% fiducial limit is 772.5-1052.1mg/Kg.
According to " Chinese clinical pharmacology and therapeutics magazine ", 1999,4 (3), report among the 237-240 that the male mice once medium lethal dose LD50 of oral Virga is 625mg/Kg, 95% fiducial limit is 50-672mg/Kg.
Claims (8)
1. compound or pharmaceutically acceptable salt thereof or its configurational isomer with general formula (I) structure:
Wherein R1 and R2 can be identical or different, can be respectively the C1-6 alkyl, and R3 is the C1-C4 fatty acyl group, or R3 is 2 methyl.
2. according to the compound of claim 1; this compound is 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7,6-dihydro-1 h-pyrazole also [4; 3-d] pyrimidin-7-ones, i.e. Xia Mian formula (I ') compound:
3. according to the compound of claim 1, this compound is 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1; 1-dimethyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7; the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones also, promptly following formula (I ") compound:
R3 is 2 methyl.
4. (preparation method of I ") compound, this method comprises the following steps: for a formula (I ') or formula
A. be raw material with the 2-ethoxybenzoic acid, in the presence of thionyl chloride, obtain 5-chlorosulfonyl-2-ethoxybenzoic acid (II) with the chlorsulfonic acid reaction;
B. with compound (II) and cis-2, the reaction of 6-lupetazin obtains 2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenylformic acid (III);
C. compound (III) chloride is obtained 2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) Benzoyl chloride (IV);
D. compound (IV) and compound (V) prepared in reaction in the presence of 4-Dimethylamino pyridine and triethylamine are obtained 4-[2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) benzoylamino]-1-methyl-3-n-propyl pyrazoles-5-methane amide (VI);
E. compound (VI) cyclization under the potassium tert.-butoxide effect obtains 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (VII) also;
F. compound (VII) selectively acylating under the acetylation reagent effect obtains 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (I ') also);
G. compound (VII) obtains under the methylating reagent effect: 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1,1-dimethyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones (I ") also.
5. pharmaceutical composition for the treatment of impotence, it contains formula as claimed in claim 1 (I) compound or pharmaceutically acceptable salt thereof or its configurational isomer and pharmaceutically acceptable carrier as activeconstituents of significant quantity.
6. according to the pharmaceutical composition of claim 5, its Chinese style (I) compound is 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1-ethanoyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7, the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones also.
7. according to the pharmaceutical composition of claim 5; its Chinese style (1) compound is 5-[2-oxyethyl group-5-(cis-2,6-lupetazin-1,1-dimethyl-4-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-7; the 6-dihydro-1 h-pyrazole is [4,3-d] pyrimidin-7-ones also.
8. each the purposes of formula (I) compound in the medicine of preparation treatment impotence disease of claim 1-3.
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