Method of producing peptides of their acid-additive salts

专利摘要:
Peptides, acid addition salts, salts, and pharmaceutical compositions thereof, and their use as morphine agonists, and especially H.Tyr.D. Met. Gly. Phe (4NO2 I. ProNH2 and H.Tyr. D.-Met(O). Gly. Phe(4NO2). ProNH2 as anti-diarrhoeals and anti-tussives.
公开号:SU1470199A3
申请号:SU782691552
申请日:1978-11-23
公开日:1989-03-30
发明作者:Вилкинсон Сэмюель
申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
IPC主号:

专利说明:

I
The invention relates to a method for producing peptides or their acid addition salts, new biologically active compounds that can be used in medicine.
The purpose of the invention is a method of obtaining new derivatives in a number of peptides of low toxicity and possessing high antidiarrheal, antitussive, and analgesic activity.
The following abbreviations are accepted: DMF - dimethylformamide; THF is tetrahydrofuran; DCC1 - dicyclohexyl- carbodiimide; HOBT - 1-oxybenzotriazole; - N-methylmorpholine DCV 2
-dicyclohexylurea; BOS - tertiary butyloxycarbonyl.
Chromatography was performed in a thin layer of silica gel on Merc plates using the following solvent systems.
2. A mixture of "-butanol, acetic acid and water in a ratio of 3: 1: 1. v 3. Chloroform: methanol: 32% acetic acid 120: 90: 40, methanol 32% ammonia 120: 90.40.
7. A mixture of chloroform, methanol and 32% aqueous solution of acetic acid in a ratio of 120: 90: 5.
8. A mixture of chloroform, methanol and
About 880 ammonia in a ratio of 120: Wu: h.
four
WITH
 S
High resolution liquid chromatography is carried out on columns: Zor-wah C-8, 4.6 mm x 25 cm, as the mobile phase
Tug
3i-het
a mixture of acetonitrile and 0.1 M ammonium acetate, pH 4.0. The flow rate of 2 ml / min, the determination at a wavelength of 254 nm,
 P1.
Example 1. H-Tyr-DMet (0) -Gly- -Phe (4NOj) ProNHa.
BOC-D-Met. Gly. OME (1).
CHA-SALT BOC-D-Meth (28.38 g) is suspended in ethyl acetate (150 ml) and the resulting suspension is mixed with a solution of KHSO. (13.5) in water (75 ml). After complete dissolution, the organic phase is separated, washed twice with water (2x60 ml), dried over anhydrous MgS04 and concentrated. The resulting oily liquid was dissolved in tetrahydrofuran (90 ml), cooled to -25 ° C and treated with N-dimethylmorpholine (6.66 g) and isobutyl chloroformate (8.60 g). The reaction mixture is stirred for 2 minutes at and then treated with a pre-cooled to -25 ° C solution of Gly (7.53 g) and N-methylmorbolin (6.06 g) in dimethylformamide (90 ml). After you
holding for 2 hours at -15 ° C, the reaction mixture is transferred to an ice bath, treated with 2 M KHCOj solution (72 ml) and stirred for 30 minutes. Thereafter, the solvent is distilled off in vacuo, and the residue is partitioned between ethyl acetate (350 ml) and water (75 ml). The organic layer is then washed with 5% citric acid solution (ml), 5% growth solution of NaHCO) (2 "50 ml) and water (ml). The extract is dried over anhydrous MgSO4 and packed; dry until then the dry residue is triturated with petroleum ether.
15
Yield: 18.12 g (94% of theory). The results of thin layer chromatography: one spot in 2.7.8.
H D-Met, Gly, OM.NS (2).
BOC-D-Met. Gly.OMe (1) (18.1 g) is suspended in anisole (150 ml) and the resulting suspension is treated with a mixture of M HCl and acetic acid (440 ml). The mixture was stirred at room temperature for 30 minutes. The resulting product is precipitated by adding dry ether, separated by filtration, and thoroughly dried with dry ether. The resulting crude product is dissolved in water (450 ml) and the solution is washed twice with ether to remove anisole residues. The aqueous solution is frozen. The result is 13.77 tons of product (yield 95% of theoretical.). The results of thin-layer chromatography: clean
product (2.7.8).
BOC, -Tyr D-Met.Gly..OMe (3). VOST-Tug (16.59 g) is dissolved in tetrahydrofuran (80 ml), cooled to -25 ° C and N-methylmorpholine (5.96 g) is added to it, and then with rapid stirring isobutyl chloroformate ( 7.69 g). After holding for 2 minutes, a pre-cooled solution of D-Met, .Gly, .MODE (13.77 g) and N-methyl chloroformate (5.42 g) in dimethylformamide (80 ml) and continue stirring at -15 ° C for 2.5 hours. The mixture is then placed in an ice bath and treated for 30 minutes with a 2 M solution of HCSO3 (65 ml). The residue obtained after distilling off the solvents in vacuo is dissolved in a mixture of ethyl acetate (360 ml) and water (70 ml). The organic phase is separated and washed with 5% citric acid solution (2-50 ml), 5% NaHCOj solution (2 "50 ml) and water (2 50 ml). After drying (MgSO4). And removing the solvent, the solid residue is triturated with ether. As a result, 21.16 g are obtained (81.6% of the results are theoreticalized by thin layer chromatography (7). It is established that the reaction ends after 45 minutes. After the reaction has ended, the methanol is distilled off in vacuum, the aqueous solution is cooled with ice and neutralized. 1 M HC1 solution (110 ml). The precipitated product is filtered off, washed several times with water and dried over Pa05. Yield: 20.18 g (98% of theory). Results of thin-layer chromatography: one 2.7 in, eight.
Calculated,%: C, 53.73; H 6.6G, N 8.96.
CiiH3, NjO-, S
Found,%: G 53.55; H 6.62, N 8.76.
BOC-Tyr.D-Met (O). Gly (5). A solution of BOC-Tyr.D-Met. Gly (5.48) 20 in methanol (120 ml) is treated
two equivalents of hydrogen peroxide (2.7 ml of 29.4% solution). The reaction is monitored by high-speed liquid chromatography. After allowing the mixture to stand at room temperature for 20 hours, it is evaporated to dryness and the residue is triturated with ether. You- xo; f: 5.46 g (96.5% of the theoretical). M.p. 186-188 ° С (with decomposition).
25
thirty
g - 5.5
formamide).
.
1.0 ° (, dimethyl- 1.3 (C 1, dimethyl formamide).,
Calculated,%: C 51.96, H 6.39, N 8.66.
C ,, H 5, Y50 „3
40
Found,%: C 52.13, H 6.38;
N 8.53.
BOC-Phe (NO, 2). Pro-Ome (c).
BOC-Phe (N05) (31.0 g) is dissolved in dimethylformamide (150 ml), then 45 are added to the resulting solution of 1-hydroxybenzotriazole (27.0 g), the mixture is cooled to -5 ° C and then dicyclohexyl urea (20.6 g) is added to it. The mixture is kept in the flow of 21.16 g (81.6% of the theoretical-. - - "; D-5 ° C, in any output of the output) -" -: ° ° ;; Ha; o-Pb-x to the nHy is added a solution of Pro-OMe, tida. According to thin-layer chromate f,.,
graphs (2,7,8), the resulting product does not contain impurities.
BOC-Tyr.D-Met. Gly (4).
  f 4 L L Ss
 L. J l. i "1-" - / l-xZ protected tripeptide (3) (21.1 g) was dissolved in a mixture of methanol (350 ml) and water (150 ml). M was saponified by treatment with 2 M NaOH solution (55 ml). The reaction proceeds kontrei1L l lsgg j, jv cijj i «t
HCl (16.55 g) and N-methylmorpholine (10.1 g) in dimethylformamide (30 ml). The reaction mixture is stirred for 20 hours at 5 ° C and then filtered from dicyclohexyl urea. After evaporation in vacuo, an oily liquid is obtained, which is dissolved in ethyl acetate (1500 ml) and
15
e eu
are cast by thin layer chromatography (7). The reaction was found to end after 45 minutes. After completion of the reaction, the methanol is distilled off in vacuo, the aqueous solution is cooled with ice and neutralized with a 1 M HC1 solution (110 ml). The precipitated product is filtered off, washed several times with water and dried over Pa05. Yield: 20.18 g (98% of theory). The results of thin layer chromatography: one spot in 2.7.8.
Calculated,%: C, 53.73; H 6.6G, N 8.96.
CiiH3, NjO-, S
Found,%: G 53.55; H 6.62, N 8.76.
BOC-Tyr.D-Met (O). Gly (5). A solution of BOC-Tyr.D-Met. Gly (5.48) 20 in methanol (120 ml) is treated
two equivalents of hydrogen peroxide (2.7 ml of 29.4% solution). The reaction is monitored by high-speed liquid chromatography. After allowing the mixture to stand at room temperature for 20 hours, it is evaporated to dryness and the residue is triturated with ether. You- xo; f: 5.46 g (96.5% of the theoretical). M.p. 186-188 ° С (with decomposition).
25
thirty
g - 5.5
formamide).
.
1.0 ° (, dimethyl- 1.3 (C 1, dimethylformamide).,
Calculated,%: C 51.96, H 6.39, N 8.66.
C ,, H 5, Y50 „3
Found,%: C 52.13, H 6.38;
N 8.53.
BOC-Phe (NO, 2). Pro-Ome (c).
BOC-Phe (N05) (31.0 g) is dissolved in dimethylformamide (150 ml), then 1-hydroxy-benzotriazole (27.0 g) is added to the resulting solution, the mixture is cooled to -5 ° C and then added dicyclohexyl urea (20.6 g) is added to it. The mixture is kept in flow - - "; G-5 ° C, in which K2Ox solution, f,.,
1i1L l lsgg j, jv cijj i «t
HCl (16.55 g) and N-methylmorpholine (10.1 g) in dimethylformamide (30 ml). The reaction mixture is stirred for 20 hours at 5 ° C. and then filtered from dicyclohexyl urea. After evaporation in vacuo, an oily liquid is obtained, which is dissolved in ethyl acetate (1500 ml) and
Prepare 5% citric acid solution (ml), 5% NaHCOj solution (2x250 ml) and half-saturated NaCl solution (2250 ml). The organic phase is dried and concentrated to 500 ml. The precipitated dicyclohexylurea is filtered off by JOT, and the filtrate is evaporated, resulting in a resin that is not identified.
H.Phe (N0.2). Pro.OMe.HCl (7), Protected dipeptide (21.41 g) / dissolved in ethyl acetate (300 ml) and the resulting solution is cooled to, after which dry hydrogen chloride gas is passed through it for 45 minutes, maintaining the temperature 0 The solution was then concentrated to 50 ml and diluted with dry ether (300 ml). After freezing, the product is filtered off, washed thoroughly with dry ether and dried over a mixture of P205 and NaOH.
Yield: 15.64 g (85% of theory.) So pl. 145-148 s.
- 15.7 (, MeON)
 J-r Lcljf 17.6 ° (, MeOH),
Calculated,%: C 50.35; H 5.59, 11.75.
BOC-Tyr.D.Met (0) .Gly.Phe (N0). .ProNH-2 (0.81 r) is suspended in anisole (14 ml) and the suspension is treated with a single-molar mixture of HC1 and acetic acid (80 ml). After holding the reaction mixture for 45 minutes at room temperature, it is evaporated to dryness and the residue is triturated with
35
CijH.NjOsCl
Found,%: C 50.03, H 5.81, N 11.45.
BOC-Tyr.D-Met (0). Gly.Phe (NO.) .Pro.OMe (8) "
Solution BOC-Tyr.D-Met (O). Gly (1.0 r) in dimethylformamide (30 ml) is OK to -5-C, after which treatment-40. The resulting product is subjected to 1-hydroxybenzotriazole K, t is purified by ion exchange.
chromatography on a column of 2, cm, filled with carboxymethyl cellulose. The elution is carried out at an Arn gradient of 0, 2 M ammonium acetate at pH 5.1. Output: 0.33 g. According to thin-layer and high-speed column liquid chromatography, the resulting product is not 45
(0.56 g) and dicyclohexylcarbodiimide (0.42 g). The mixture is stirred for 40 minutes at, then a solution of Phe (NO / |) .Pro. OMe.HCl (0.74j and N-methylmorpholine (0.21 g) in dimethylformamide (5 ml) is added to it and the reaction is carried out combinations at 5 ° C for 20 hours. The precipitated dicyclohexylurea is filtered to remove impurities, discharged, and the filtrate is concentrated in a vacuum.The crude product is partitioned between ethyl acetate (100 ml) and water (20 ml). citric acid solution (ml), 5% NaHCO solution (ml) and water (ml), dried over anhydrous MgSO4, and evaporated, resulting in an amorphous
Calculated,%: C 51.15; H 6.00, N 13.05.
СзоН „Ы70-СН5СО.
Found,%: C 50.83; H 6.06 N 12.91,
Rf 0.53-, 0.13
 MD 6.3 (, 2). Rf 0.32, 0.65 0.64.
ten
) 25
4701998
the solid residue, which, after grinding with ether, weighs 1.0 g (62% of the theoretical yield). According to thin layer chromatography (2), some dicyclohexyl urea is present in the resulting product. no further purification was carried out,, BOC-Tyr.D-Met (O) .Gly.Phe (N0). .Pro-NH, (9).
The fully protected pentapeptide (1.0 g) is dissolved in methanol (150 ml), the solution is cooled in a mixture of ice and salt and saturated with ammonia. 5 After this, the flask was closed and the mixture was left for 6 days at room temperature. Then, after thoroughly removing the ammonia and methanol, the resulting product is extracted with a mixture of ethyl acetate and sulfur. Yield: 0.81. g (83% of theoretical.). According to thin layer chromatography (2.7.8), the resulting product contains some amount of dicyclohexyl urea and a small amount of starting material. The resulting product is used in the next step without further purification.
20
H.Tyr.D-Met (0) .Gly.Phe (N0). .PrONH ,, (10).
BOC-Tyr.D.Met (0) .Gly.Phe (N0). .ProNH-2 (0.81 r) is suspended in anisole (14 ml) and the suspension is treated with a single-molar mixture of HC1 and acetic acid (80 ml). After holding the reaction mixture for 45 minutes at room temperature, it is evaporated to dryness and the residue is triturated with
 The resulting product is subjected to, t cleaning using ion-exchange
keeps impurities
Calculated,%: C 51.15; H 6.00, N 13.05.
СзоН „Ы70-СН5СО.
Found,%: C 50.83; H 6.06 N 12.91,
Rf 0.53-, 0.13
 MD 6.3 (, 2). Rf 0.32, 0.65 0.64.
Example 2 (see diagram 2). BOC-Phe (N0j) .Pro.NH7 (11). BOC-Phe (NOa) .Pro.Ome (6) (22.9 g solution of 1gt in methanol (250 ml) and cool the resulting solution with ice, after which the gaseous ammonia is passed through it until it is napped. Then the flask is closed and left at room temperature for 7 days. After that, the reaction mixture is evaporated in vacuo and the crude product is subjected to crystallization from ethyl acetate. According to thin-layer and high-speed liquid chromatography, the resulting solution does not contain impurities T, pl. WITH.
UlV - 29.4 ° (,). , 35.7 (, MeOH). Calculated,%: C 56.16, H 6.40, N 13.79.
C ,, H jN4vJt.
Found%: C 55.60, H 6.33,
N 14.04.,.
H.Phe (NO.). Pro (12) BOC-Phe (N0). Pro.NH-2 (8.0 g) was dissolved in a mixture of methanol (20 ml), isopropanol (40 ml) and ethyl acetate (375 ml). The resulting solution is cooled with ice and HCl gas is passed through it for an hour, keeping the temperature at -15 C.
Thereafter, nitrogen is passed through the reaction mixture for 5 minutes and diluted with dry ether.
Scheme 2
Pro
Ome
/five

(450 ml). The resulting product is filtered, washed thoroughly with ether and dried in vacuo over the mixture and NaOH. The output of 6.28 g (93% of theoretical). M.p. 156-15J O.
 13.5 15.3
(, Meon). (, Meon).
five
0

Jq jj
five
BOC-Tyr.D-Met.Gly.Phe (NO) .Pro. NH-2 (13).
 BOC-Tyr.D-Met (0). Gly (5) (1.0 g) is dissolved in dimethylformamide (20 ml) and the resulting solution is cooled to -25 ° C, after which N-methylmorpholine (0, 21 g) and isobutyl chloroformate (0.28 g) and the mixture is intensively stirred for 2 minutes, maintaining its temperature equal to -15 ° C. Then, a solution of Phe (NO-2) .Pro.NHa.HCl (0.71 g) and N-methylmorpholine (0.33 g), which was previously cooled to -25 ° C, was added to it and stirred at -15 ° C for 2 , 5 hours. After that, the reaction mixture is transferred to an ice bath and treated with 2M KHCO3 (2.5 ml) for 30 minutes. The solvents are distilled off in vacuo, and the residue is partitioned between ethyl acetate (270 ml) and water (40 ml). The organic phase is separated and washed with 5% citric acid solution (ml), 5% NaHCOj solution (240 ml) and water (2 x 40 ml). The extract is dried and evaporated to dryness. After grinding the residue with ether, 0.56 g of product is obtained (35% of the theoretical yield). The resulting product is used in the next step without further purification.
 H.Tyr.D-Met (O) .Gly.Phe (N0) .Pro
.NHjCU),
From BOC-Tyr.D-Met (O) .Gly.Phe (NOj)
..Pro.NHa (0.56 r) cleaves the protective group in a mixture of HC1 and acetic acid (56 ml) in the presence of anisole (20 ml). After 30 minutes at ambient temperature, the reagents are removed in vacuo and the resulting crude product is triturated with ether. The resulting crude product is chromatographed on a column of 2.5 to 25 cm filled with carboxymethylcellulose. The elution is carried out with a linear gradient of 0.005-0.2 M ammonium acetate at pH 5.1. After this pre-purification, the peptide is again returned to column 2, cm, filled with carboxymethylcellulose, and elution with ammonium acetate with a linearly varying concentration from 0.005 to 0 , 1 M at pH 5.1. After removal of the volatile buffer by repeated freeze-drying, the pure peptide is obtained. Yield: 50 mg (91% of theoretical). According to thin-layer (2,7,8; and high-speed column liquid chromatography, the resulting product does not contain impurities.
Calculated,%: C 50.52, H 6.05 ,; N 12.89.
SzsNezM OEZ-SNDSOGN 1.5 Found,%: C 50.59; H 5.96;
N 12.97.
Example 3. H-Tyr-DMet Gly-Phe (4NO Profflii was prepared according to the scheme outlined above. The product was isolated as an acid chloride salt and then purified on carboxymethyl cellulose (CMC 52) by gradient elution with ammonium acetate solution (0.001-M to 0.5 M). After lyophilization, an acetic acid salt is obtained from the aqueous solution.
Rf: 0.52, 0.83 0 „47"
. “8.1, (, 2 MeOH).
Pharmacological actibility.
The peptides of the indicated examples were tested for the following types of activity.
five
0
five
0
using standard pharmacological methods.
Analgesic in mice when tested with a hot plate, the peptide being administered by injection into the cerebral ventricle.
Antidiarrheal activity in rats. In this method, the rats go hungry for 24 hours, then the peptide is administered subcutaneously or orally, after which, after 15 minutes, castor oil is given orally 1 ml per rat (EDjo - 0.02-0.03 mg / kg).
For anticalcosis, guinea pigs were exposed to an aerosol containing 20% citric acid 30 minutes after the administration of the compound (orally or subcutaneously). The number of coughs was calculated during the five minute exposure and the values were averaged for six animals in the experiment (EDjo-10 mg / kg P.O.). .
Analgesia in mice with spasm (modification of Henderson et al.) When administered orally with peptide.
Their main purpose is the treatment of diarrhea.
When tested on rats for syn-, labeled peptides and morphine, the following EDjo values (see table) 5 characterizing their analgesic activity were obtained.
The peptides under test, the chickens are of low toxicity — when administered individually orally to five mice in an amount of 500 mg / kg, none of the mice died.
The compounds of the invention are low toxic, have high antidiarrheal, analgesic and antispasmodic activity.

权利要求:
Claims (1)
[1]
The formula of the invention. A method for producing peptides of the formula
H-Tyr-X-Gly-Phe (4NO) Pro-NH, where X-DMet, DMet (O),
131470199
or their acid additive salts, e Y NH20Me,
characterized in that "the resulting Pentapeptide Tripeptide Formula
BOC-Tyr-X-Gly-Phe (4N05) -ProY,
BOC-Tyr-X-GlyOH, 5 g if necessary, if Y-OMe,
where X-DMet or DMet (O) is treated with ammonia with ammonia treatment
interact with the dipepty group on the amino group, then remove the formula “the protective group and the target
The IQ product is isolated in free form H-Phe (4NO.j) ProY, and gc g as an acid additive salt.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1470199A3|1989-03-30|Method of producing peptides of their acid-additive salts

---

US4086219A|1978-04-25|Nonapeptides and methods for their production

---

US4242329A|1980-12-30|Bradykinin-inhibiting tripeptide derivatives

---

US4178371A|1979-12-11|Tetrapeptide derivatives

---

FI73224B|1987-05-29|FOERFARANDE FOER FRAMSTAELLNING AV NYA, PAO DEN CENTRALA NERVSYSTEMET INVERKANDE TRIPEPTIDER.

---

US3705140A|1972-12-05|Peptides related to the c-terminal sequence of cck-pz and caerulein

---

US5013723A|1991-05-07|New thymopentin retro-inverso analogs and fragments thereof, a process of preparation of the new compounds and the intermediates obtained therein

---

US3579494A|1971-05-18|C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin |

---

HU182866B|1984-03-28|Process for preparing new tetrapeptide derivatives

---

CH636598A5|1983-06-15|METHOD FOR PRODUCING NEW PSYCHOPHARMACOLOGICALLY ACTIVE PEPTIDES.

---

US4124703A|1978-11-07|Luliberin analogs

---

US4320051A|1982-03-16|Analgesic tripeptide amides

---

CA1059994A|1979-08-07|Histidine derivatives

---

FR2557114A1|1985-06-28|NOVEL DERIVATIVES OF GONADOLIBERIN, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

---

US4111923A|1978-09-05|Octapeptides and methods for their production

---

Stewart1981|Peptide synthesis with 1-Aminocyclopropane-1-carboxylic acid

---

DE2324239C3|1975-05-28|Process for the preparation of biologically active polypeptides containing asparaginyl groups

---

US4093713A|1978-06-06|Dipeptide derivatives with central nervous system activity and preparation thereof

---

DE2342862C3|1981-01-15|Peptides with ACTH action containing residues of α-aminooxycarboxylic acids at both chain ends, process for their preparation and pharmaceuticals containing these peptides

---

US4579841A|1986-04-01|Dipeptide derivatives having opiate activity

---

US3790555A|1974-02-05|Octapeptide derivative of gonadotropinreleasing hormone

---

Poojary et al.2005|Synthesis, characterization and biological evaluation of cyclic peptides: viscumamide, yunnanin A and evolidine

---

US4271152A|1981-06-02|Psycho-pharmacological peptides

---

US3417072A|1968-12-17|Intermediates in the synthesis of secretin

---

RU2043769C1|1995-09-20|Process for preparing peptide

同族专利:

---

公开号 | 公开日

---

HU186729B|1985-09-30|

---

ZA786598B|1980-06-25|

---

CA1197235A|1985-11-26|

---

US4362717A|1982-12-07|

---

PL123797B1|1982-11-30|

---

AU4186578A|1979-05-31|

---

AT386211B|1988-07-25|

---

IE47517B1|1984-04-04|

---

DE2862477D1|1986-03-20|

---

US4343795A|1982-08-10|

---

IE782317L|1979-05-24|

---

US4346083A|1982-08-24|

---

ATA836278A|1987-12-15|

---

US4244944A|1981-01-13|

---

JPS5492938A|1979-07-23|

---

DK523078A|1979-05-25|

---

IL56028A|1984-03-30|

---

DK149612B|1986-08-11|

---

KR880002609B1|1988-12-04|

---

IT1106143B|1985-11-11|

---

PL211164A1|1979-12-17|

---

EP0002236B1|1986-02-05|

---

EP0002236A1|1979-06-13|

---

JPS6318600B2|1988-04-19|

---

AU530985B2|1983-08-04|

---

KR880002608B1|1988-12-04|

---

MY8500260A|1985-12-31|

---

IL56028D0|1979-01-31|

---

ES475324A1|1979-12-01|

---

FI70415C|1986-09-19|

---

US4363800A|1982-12-14|

---

KR860000453B1|1986-04-26|

---

GB1604850A|1981-12-16|

---

KR830000215A|1983-03-30|

---

DK149612C|1987-01-26|

---

FI70415B|1986-03-27|

---

KR830000214A|1983-03-30|

---

FI783589A|1979-05-25|

---

KR830000683A|1983-04-18|

---

IT7852041D0|1978-11-23|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

NZ183712A|1976-04-08|1979-10-25|Ici Ltd|Polypeptide analogues of enkephalins, and pharmaceutical compositions|

---

US4028319A|1976-05-07|1977-06-07|G. D. Searle & Co.|2 and 3-substituted enkephalins|

---

US4123523A|1976-06-21|1978-10-31|Imperial Chemical Industries Limited|Analgesic and sedative polypeptides|

---

FR2359817B1|1976-07-27|1981-01-02|Reckitt & Colmann Prod Ltd|

---

GB1577115A|1976-07-27|1980-10-22|Reckitt & Colmann Prod Ltd|Container closure units|

---

US4092304A|1976-08-09|1978-05-30|G. D. Searle & Co.|4-Substituted enkephalin derivatives|

---

SE7709806L|1976-09-01|1978-03-02|Coy David Howard|PROCEDURE FOR PREPARING PEPTIDES|

---

HU178001B|1976-09-16|1982-02-28|Gyogyszekutato Intezet|Process for preparing new pentapeptides with morphine-like activity and derivatives thereof|

---

US4128541A|1976-12-27|1978-12-05|American Home Products Corporation|Pentapeptide with morphine- like activity|

---

DE2819277A1|1977-05-16|1978-11-23|Sandoz Ag|NEW POLYPEPTIDE DERIVATIVES, THEIR PRODUCTION AND USE|

---

US4127532A|1977-06-16|1978-11-28|Coy David Howard|Novel heptapeptides, intermediates therefor, and compositions and methods employing said heptapeptides|

---

US4127531A|1977-06-16|1978-11-28|Coy David Howard|Novel hexapeptides, intermediates therefor, and compositions and methods employing said hexapeptides|

---

US4127523A|1977-06-16|1978-11-28|Coy David Howard|Novel undecapeptides, intermediates therefor, and compositions and methods employing said undecapeptides|

---

US4127533A|1977-06-16|1978-11-28|Coy David Howard|Novel octapeptides, intermediates therefor, and compositions and methods employing said octapeptides|

---

US4103005A|1977-10-20|1978-07-25|Hoffmann-La Roche Inc.|Novel-enkephalin analogs|

---

GB1604850A|1977-11-24|1981-12-16|Wellcome Found|Biologically active peptides|DK28377A|1976-02-02|1977-08-03|Sandoz Ag|PROCEDURE FOR PREPARING POLYPEPTIDE DERIVATIVES|

---

GB1604850A|1977-11-24|1981-12-16|Wellcome Found|Biologically active peptides|

---

DE3163199D1|1980-07-17|1984-05-24|Sandoz Ag|Novel pentapeptides, processes for their production, pharmaceutical compositions comprising said pentapeptides and their use|

---

EP0076557B1|1981-06-22|1985-11-13|Imperial Chemical Industries Plc|Peptides and pseudopeptides in which the n terminus bears two substituents|

---

US4380535A|1981-09-23|1983-04-19|American Home Products Corporation|Enkephalin degrading enzyme inhibitors|

---

US4492779A|1981-12-07|1985-01-08|Thiokol Corporation|Aramid polymer and powder filler reinforced elastomeric composition for use as a rocket motor insulation|

---

EP0085963B1|1982-02-05|1987-01-21|The Wellcome Foundation Limited|Pharmaceutical compounds, preparation, use and intermediates therefor and their preparation|

---

AT37552T|1982-10-18|1988-10-15|Ici Plc|PEPTIDE AND PSEUDOPEPTID DERIVATIVES.|

---

JPH0680079B2|1984-11-09|1994-10-12|エーザイ株式会社|Polypeptide|

---

GB8608818D0|1986-04-11|1986-05-14|Reckitt & Colmann Prod Ltd|Pharmaceutical compositions|

---

GB8616741D0|1986-07-09|1986-08-13|Wellcome Found|Pharmacologically active compounds|

---

US5688519A|1987-04-06|1997-11-18|Leonard; Robert J.|Flash-flow fused medicinal implants|

---

US5156787A|1991-01-29|1992-10-20|Booher Benjamin V|Pultrusion method of making brake linings|

---

USRE37548E1|1991-08-12|2002-02-19|Bill J. Hays|Clutch design and manufacture|

---

US5482772A|1992-12-28|1996-01-09|Kimberly-Clark Corporation|Polymeric strands including a propylene polymer composition and nonwoven fabric and articles made therewith|

---

US6488649B1|1998-11-24|2002-12-03|Edward M. Lichten|Implant device|

---

IL165365D0|2004-11-24|2006-01-15|Q Core Ltd|Finger-type peristaltic pump|

---

DE112007000840A5|2006-04-21|2009-01-02|Luk Lamellen Und Kupplungsbau Beteiligungs Kg|Multilayer, in particular two-layer clutch lining and method for its production|

---

US8005603B2|2007-09-27|2011-08-23|Continental Controls Corporation|Fuel control system and method for gas engines|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

GB48980/77A|GB1604850A|1977-11-24|1977-11-24|Biologically active peptides|

---