GB2050359A - Derivatives of mercaptoacyl amino acids - Google Patents
Derivatives of mercaptoacyl amino acids Download PDFInfo
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- GB2050359A GB2050359A GB8014648A GB8014648A GB2050359A GB 2050359 A GB2050359 A GB 2050359A GB 8014648 A GB8014648 A GB 8014648A GB 8014648 A GB8014648 A GB 8014648A GB 2050359 A GB2050359 A GB 2050359A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
<IMAGE> and alkyl esters and salts thereof, wherein R1 is hydrogen, alkanoyl or benzoyl, R2 is hydrogen, alkyl or trifluoromethyl, n is 0 or 1 and A1 and A2 each is an alpha -amino or alpha -imino acid residue, have hypotensive activity and can be incorporated into pharmaceutical compositions.
Description
SPECIFICATION
Derivatives of mercaptoacyl amino acids
Compounds having the formula
and alkyl esters and salts thereof, are inhibitors of the action of angidtensin-converting enzyme, and can be used to treat hypertension. In formula 1, and throughout the specification, the symbols are as defined below.
R1 is hydrogen, alkanoyl, or benzoyl;
R2 is hydrogen, alkyl ortrifluoromethyl; n isO or 1; and A1 and A2 each is an amino or amino acid residue. The As residue is linked to the R1 group through the amino or a-imino group and linked to the sulfur atom through the carboxyl group. The A2 residue is joined to the adjacent carbonyl group through its a-amino or amino group.
The term "alkyl", as used throughout the specification, refers to groups having 1 to 7 carbon atoms.
The term "alkanoyl", as used throughout the specification, refers to alkanoyl groups having 2 to 7 carbon atoms. Acetyl is the preferred alkanoyl group.
The a-amino and amino acid residues represented by A1 and A2 can be either naturally occurring or synthetic. Exemplary groups are proline, 4-hydroxyproline, 4-chioroproline, 4-fluoroproline, 4,4difluoroproline, 4,4-ethylene-dioxyproline, 4-methoxyproline, 4-thiazolidine-carboxylic acid, tryptophane, glycine, alanine, leucine, isoleucine, valine and phenylalanine.
Preferred compounds of this invention are those having the formula
and alkyl esters and salts thereof. In formula 11, and throughout the specification, R3 is hydrogen orfluoro and R4 is hydrogen, hydroxy, methoxy, chloro, or fluoro, or together with the carbon atom to which they are attached R3and R4 form an ethylenedioxygroup.
Those compounds of formula I wherein the a-amino or ct-imino residues of A1 and A2 are in the
L-configuration are also preferred.
The products of this invention can be prepared by first reacting an amino or ct-imino acid (with protected nitrogen atom) having the formula Ill
Rs-A7 with a mercaptoacyl amino acid having the formula
IV R2
HS-(CH2),-CH-C-A2, 0 or an alkyl ester thereof: The particular F5 nitrogen protecting group used is not critical; exemplary of the known protecting groups are t-butyloxycarbonyl, benzylbxycarbonyl, and o-nitrophenylsulfenyl. Any other nitrogen protecting group that can later be removed under mild conditions can also be used, provided that it protects against racemization of A1 during the activation step described below.The F5 group can of course also be alkanoyl or benzyol as defined in R1, although these groups are not considered protecting groups in the sense that they are not as easily removable as the above-mentioned protecting groups and may not afford protection against racemization.
The above reaction yields a compound having the formula
or alkyl ester thereof, and is carried out by first activating the carboxyl group of a compound of formula III, using art-recognized procedures. For example, activation can be accomplished by reaction of a compound of formula III with N,N'-carbonyl-bis-imidazole or with a mixture of base and alkylchloroformates. The reaction of a compound of formula III (with activated carboxyl group) can be accomplished in an organic solvent, e.g., a halogenated hydrocarbon, preferably in the presence of an organic base. Reaction conditions are not critical, and the reaction can conveniently be carried out at room temperature.
The blocking group 'R5" can be removed from a compound of formula V, using art-recognized procedures, to yield the corresponding product of formula I wherein R1 is hydrogen. Those products of formula I wherein R1 is alkanoyl or benzoyl caN also be prepared from a product wherein Rt is hydrogen by reaction with the appropriate alkanoic acid anhydride or benzoyl halide respectively.
The starting materials of formula IV, and methods for their preparation, are described in the literature; see, for example, United States patents 4,046,889, 4,105,776 and 4,053,651. As described therein an a-amino or amino acid (A2) can be coupled with a haloalkanoic acid of the formula
wherein Xis a halogen, preferably chlorine or bromine, by one of the known procedures in which the acid VI is activated, prior to reaction with the acid "A2", involving formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester or use of Woodward reagent K, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2dihydroquinoline) or the like.The product of this reaction is a compound of formula
VII R2 X-(cH2)n-cH-c-A2 - 0
Subjecting a compound of formula Vll to a displacement reaction with the anion of a thioacid of the formula
VIII O R6-C-SH, wherein F6 is alkyl, aryl or arylalkyl, yields a compound having the formula
IX O R2 R6-c-s-(cH2)n-cH-c-A2 / 0 which can then be converted to the mercapto compound of formula IV by ammonolysis. The art also discloses several alternative processes for preparing the compounds of formula IV.
The compounds of this invention form basic salts with various organic and inorganic bases which are also within the scope of this invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids like arginine, Iysine and the like. The nontoxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The compounds of formula 1, and the alkyl esters and salts thereof, may be used as hypotensive agents.
They inhibit the conversion of the decapeptide angiotensin i to angiotensin II and, therefore may be used in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudo-globulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs.The compounds of this invention intervene in the angiotensinogen < (renin) ,angiotensin l~(ACE) ,angiotensin il sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one or a combination of compounds of formula I, angiotensin dependent hypertension in the species of mammal suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day, preferably about 1 to 50 mg. per kilogram of body weight per day is appropriate to reduce blood pressure.The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of formula I can be formulated with a pharmaceutical carrier for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I may be compounded with a physiologically acceptable vehicle. carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Depending on the nature 9f the "R" substituents, the products of formula I may have one or more asymetric carbons and, therefore, exist in stereoisomericforms or in racemic mixtures thereof. All of these are within the scope of this invention. In the above described syntheses, one of the enantiomers or the racemate can be used as the starting material. When the racemic starting material is used, the stereolsomers obtained in the product can be separated by conventional techniques; e.g., chromatography or fractional crystallization.
The following examples are specific embodiments of this invention.
EXAMPLE 1 (S)- 1-[3-[( 1-A cetyl-L-prolyl)tbio].2-methyl- I-oxoprop yl]-L-proline A) (5)-1-[3-[[1-rt-Butyloxycarbonyl)-L-prolyl]thio]-2-methyl-1-oXopropyl/-L-proline (t-Butyloxycarbonyl)-L-proline (1.2909) is taken into 10 ml. of dichloromethane with stirring in an ice bath;
N,N'-carbonyl-bis-imidazole (972mg) is added. After 1 hour, (S)-1-(3-mercapto-2-methyl-1-oxoprnpyl)-L- proline (1.085g) in 5 ml. of dichloromethane and 0.7 ml. of triethylamine is added. After an additional hour, the ice bath is removed and the reaction is allowed to proceed for about 16 hours at room temperature. The dichloromethane is removed in vacuo and the residue is taken into ethyl acetate and washed with 10% potassium sulfate, yielding 2.4 g of material.This material is purified on a silica gel column which is eluted with ethyl acetate: buffer (200:37; buffer is pyridine: acetic acid: water, 20:6:11). The pooled fractions are taken into ethyl acetate and washed with 10% potassium sulfate yielding 1.8 g of the title compound.
B ((S)- I-[3-N ) cetyl-L-proly/)thio]-2-rneth yI- 1-oxopropyll-L-proline (S)-1-[3-[[1-(t.Butyloxycarbonyl)-L.prolyl)thio]-2-methyl-1-oxopropyl(-L-prolI.ne (1.8g) is treated for 15 minutes at room temperature in 5 ml. of trifluoroacetic acid and 5 mi. of anisole. The reaction mixture is concentrated in vacuo and treated twice with ether: hexane. The residue is dried over potassium hydroxide in vacuo, and acetylated in 10 ml. of anhydrous pyridine using 0.41 ml. of acetic anhydride for 2 hours. The reaction mixture is concentrated in vacuo, water is removed twice, and the residue is lyophilized.Purification on sulfonated polystyrene cation exchange resin using water as eluant, followed by crystallization from ethyl acetate: ether yields 700 mg. of the title compound, melting point 81-83-C.
EXAMPLE 2 (S)- i-[2-[(i-A cetyl-L-prolyl)thio]- 1-oxopropyl7-L-proline A) (S)- 1-[2-[[1-{t-Butyloxycarbonyl)-L-prolylYthio 7-oxopropylj-L-proline (t-Butylocycarbonyl)-L-proline (1.075g) is taken into 10 ml. of dichioromethane and chilled with stirring in an ice bath; N,N '-carbonyl-bis-imidazole (810 mg.) is added. After 1 hour,S-1 -(2-mercapto-2-methyl-1.
oxopropyl)-L-proline (1.01 5g) in 5 ml. of dichloromethane and 0.7 ml. of triethylamine is added. After an additional hour, the ice bath is removed and the reaction is allowed or proceed for about 16 hours at room temperature. The mixture is concentrated in vacuo, taken into ethyl acetate and washed with 10% potassium sulfate, yielding 2.0 g of material. The material is purified on a silica gel column which is eluted with ethyl acetate: pyridine: acetic acid: water (120:20:6:11) and crystallized from ethyl acetate: hexane (1:21 yielding 1.076 g, melting point 143-144-C.
B) {S)- 1-[2-[(1-Acetyl-L-prolyl)thiol- 1-oxopropyl7-L-proline (S)-1 -[2-[[1 -(t-Butyloxycarbonyl)-L-prolyl]thio]-l -oxopropyl]L-proline (1.0769) is treated for 15 minutes at room temperature with 5 ml. of trifluoroacetic acid and 2 ml. of anisole. The reaction mixture is concentrated in vacuo and treated twice with ether: hexane. The residue is dried over potassium hydroxide in vacuo and acetylated for 2.5 hours in 5 ml. of an hydros pyridine with 0.23 ml. of acetic anhydride. The reaction mixture is concentrated to dryness in vacuo and lyophilized from water. Purification on sulfonated polystyrene cation exchange resin followed by lyophilization yields 700 mg. of the title compound.
EXAMPLE 3 (S)- 1-[2-[(1-Acetyl-L-phenylalanyl)thio]-1-oxopropyl]-L-proline
A) (S)- l-f2-ffN- (t-Butyloxycarbon yl)-L-ph en ylalan yljthioj- 1-oxopropyll-L-proline (t-Butyloxycarbonyl)-L-phenylalanine (1.325g) is taken into 10 ml. of dichloromethane and chilled with stirring in an ice bath; N,N'-carbonyl-bis-imidazole (810mg) is added. After 1 hour, (S)-1-(2-mercapto.1- oxopropyl)-L-proline (1.01 5g) in 5 ml. of dichloromethane and 0.7 ml. of triethlamine is added. After an additional hour the ice bath is removed and the reaction is allowed to proceed for about 16 hours at room temperature. The mixture is concentrated in vacuo, taken into ethyl acetate and washed with 10% potassium sulfate, yielding 2.3 g of material.The material is purified on a silica gel column which is eluted with ethyl acetate: buffer (120:37; buffer is pyridine: acetic acid: water. 20:6:11) and crystallized from ether: hexane to yield 1.553-9 of the title compound, melting point 59-62 C.
B) (S2- 1-[2-[(N-Acetyl-L-phenylalanyl)thio]- 1-oxopropyl7-L-proline (S)-1 -[2-[N-(t-Butyloxycarbonyl)-L-phenylalanyl]thio]-1-oxopropyl]-L-proline (1.5539) is treated for 15 minutes at room temperature with 6 ml. of trifluoroacetic acid and 3 ml. of anisole. The reaction mixture is concentrated in vacuo and the residue istritutated with ether to yield 1.1 g of material. This material is acetylated for2 hours at room temperature in 6 ml. of an hydrous pyridine with 0.28 ml. of acetic anhydride, concentrated in vacuo, taken into ethyl acetate and washed with 10% potassium sulfate. The organic layer is dried and taken to dryness in vacuo. The residue is crystallized from ethyl acetate, yielding 600 mg. of the title compound, melting point 191-192"C.
EXAMPLE 4 (SJ- 1-[3-[(1-Benzoyl-L-prolyl)thio]-2-methyl- 1-oxoprop yl]-L -pro fine By substituting benzoyl chloride for the acetic anhydride in the procedure of Example 1, the title compound is obtained.
EXAMPLE 5 (SJ- l-f3-f( i-A cetyl-L-tryp toph yl)thio]-2-rn ethyl- 1-oxopropyll-L-proline By substituting t-butyloxycarbonyl-L-tryptophan for the t-butyloxycarbonyl-L-proline in the procedure of
Example 1, the title compound is obtained.
EXAMPLE 6 (SJ- l-[3-[( 7-A cetyl-L4soleucyl)thio]-2-rneth yl- 1-oxoprop yil-L-p roline By substituting t-butyloxycarbonyl-L-isoleucine for the t-butyloxycarbonyl-L-proline in the procedure of
Example 1, the title compound is obtained.
EXAMPLE 7 (S)- 7-[3-[(l-Acetyl-F-phen ylalanyllthio]-2-meth y/- I-oxoprop y-L-4, 4-eth ylenedioxyprolin e By substituting t-butyloxycarbonyl-L-phenyl-alanine for t-butyloxycarbonyl-L-proline and 5-1 -(3- mercapto-2-methyl-1 -oxopropyl)-L-4,4-ethylene-dioxyproline for the S-1 -(3-mercapto-2-methyl-1 - oxopropyl)-L proline in the procedure of Example 1, the title compound is obtained.
EXAMPLE 8-28
Following the procedure of Example 1, but substituting the amino acid derivative listed in column I for t-butyloxycarbonyl-L-proline and the compound listed in column II for (S)-1-(3-mercapto-2-methyl-1 oxoprnpyl)-L-prnline, yields the compound listed in column Ill.
As used below the symbol Boc refers to t-butyloxycarbonyl and the symbol Ac refers to acetyl. The other symbols are standard nomenclature.
Example Column I Column II Column III '3 8 Boc-Gly Ac-Gly-SCHZCHCO-N IH3 ( ) CH3 ) 9 Boc-Val CH3 Ac-Val-SCH CcIHc3 S I CO2H 2 O-NO2H C Boc-Val HS-CHZCHCO-N H3 5 CH 3S 10 Boc-Phe Cì 3 ( ) HS-CHZCHCO-I CO2H Ac -Phe -S -CHZCHC CF CF 11 Boc-Ala HS-CH2-CHCO-NO2H Ac-Ala-S-CH2CHCO-N 2 CO H pCH3 Ac-Leu-S-CH: CH3 CH Cl 3 < 1 3 m 12 Boc-Leu HS-CH2-CHCO-N 02H Ac-Leu-S-CH2CHC3O-N%H Example Column I Column II Column III F F CH3 CH3 13 Boc-Trp HSH2-CH-CO-N CO2H Ac-Trp-S-CH2CHCO-02H F F F F CH CH 14 Boc-Ile HS-CH2CHCO- ss O2H Ac-Ile-S-CH2CHCO- H OH OH CH CH 3 15 Boc-Phe HS-CH2CHCO-N t CO2H Ac-Phe-S-CH2CHCO-NO2H C1 C1 C1H3 CH3 16 Boc-Phe HS-CH2CHCO- A CO2H Ac-Phe-S-CH2CHCO- A CO2H S CH3rs CH 17 Boc-Gly HS-CHCO-NCO2H Ac-Gly-S-CHcO- CO2H
Example Column I Column II Column III 18 Boc-Ala HS-CHCO- m o2H Ae-Ala-S-CHCO-N( m Th I 0 CE3 CE3 19 Boc-Leu HS-CHCO-N ) CO2H Ac-Ieu-S-C1HCO-CO2H Th H CH ffi 1 3 ffi CH 20 Boc-Phe HS-CHCO-N- CO2H Ac-Phe-S-CHC3O-CO2E Th Th CE CE 3 m 3 21 Boc-Trp ES-CHCO-N C02H Ac-Trp-S-CHCO-NCO2E Th Ac-Trp-S-C2CO Th 22 Boc-Trp HS-CH2CO- CO2H Ac-Trp-S-CH2CO- CO2X Example Column I Column II Column III OH OH C1E3 CH3 23 Boc-Phe ES-CECO- CO2H Ac-Phe-S-CHco-NCo2H C1 C1 CH3 A IH3 L 24 Boc-Val HS-CHCO-N 3 -COZH Ac-Val-S-CHCC ES-CECO-N CO2H 25 Boc-Ile HS-CHCO-N 2 CF Ae-Ile-S-CHCO-N CO2H F F CH 26 Boc-Leu ES-CHCO-N OH cIeu5CcHc30Lc0 2 2 F F FF CH3 ss CE3 27 Boc-Phe HS-CHCO-N 02E Ac-Phe-S-CHCO-N%E SOCH3 OCH3 28 Boc-Trp HS-CHCO- ss CO2H Ac-Trp-S CE3 -CHCO-NCO2H
EXAMPLE 29 (SJ- 1-[2-[(N-Acetyl-L-tryptophylJthiol- 1-oxoprop yl]-L-proline By substituting t-butyloxycarbonyl-L-tryptophan or the t-butyloxycarbonyl-L-phenylalanine in the procedure of Example 3, the title compound is obtained.
Claims (21)
1. Acompound having the formula
or such a compound in alkyl ester or salt form, wherein R1 is hydrogen, alkanoyl or benzoyl; R2 is hydrogen alkyl ortrifluoromethyl; n is O or 1; and A1 and A2 each is an amino or ct-imino acid residue, wherein the A1 residue is linked to the R1 group through the amino or a-imino group and linked to the sulfur atom through the carboxyl group, and wherein the A2 residue is linked to the adjacent carbonyl group through its amino ora-imino group.
2. A compound in accordance with claim 1, wherein R1 is hydrogen.
3. A compound in accordance with claim 1 wherein R1 is alkanoyl.
4. A compound in accordance with claim 1, wherein R1 is benzoyl.
5. A compound in accordance with claim 1 wherein R2 is hydrogen.
6. A compound in accordance with any one of claims 1 to 4, wherein R2 is alkyl.
7. A compound in accordance with any one of claims 1 to 4, wherein R2 is trifluoromethyl.
8. A compound in accordance with any preceding claim, wherein n is G.
9. A compound in accordance with anyone of claims 1 to 7, wherein n is 1.
10. A compound in accordance with any preceding claim, wherein A1 and A2 each is 4-fluoroproline, 4,4-difluoroproline, 4,4-ethylenedioxyproline, 4-methoxy-proline, 4-thiazolidinecarboxylic acid, tryptophane, glycine, alanine, leucine, isoleucine, valine or phenylalanine.
11. A compound in accordance with claim 10, wherein the a-amino or ct-imino residues of A1 and A2 are in the L-configuration.
12. A compound in accordance with claim 1 having the formula
or an alkyl ester of salt thereof, wherein R1 is hydrogen, alkanoyl or benzoyl; R2 is hydrogen alkyl or trifluoromethyl; F3 is hydrogen orfluoro and R4 is hydrogen, hydroxy, methoxy, chloro orfluoro ortogether with the carbon atom to which they are attached, R3 and F4 form an ethylenedioxy group.
13. The compound in accordance with claim 1, (S)-1-[3-f(l -acetyl-L-prolyl)thio]-2-methyl-l -oxopropyl]-L- proline.
14. The compound in accordance with claim 1, (S)-1-[2-[(1-acetyl-L-prolyllthio(-1-oxopropyl]-L-proline.
15. The compound in accordance with claim 1, (S)-1-[2-[(N-acetyl-L-phenylalanyl)thio]-1-oxopropyl-L- proline.
16. Acompound oftheformula R2
Rs~A1~S~(CH2)n~CH~C~A2 0 wherein An, A2, R2 and n are as defined in claim 1 and RE is a nitrogen atom protecting group.
17. A compound in accordance with Claim 1 or 16 as named or shown in any of the Examples.
18. A pharmaceutical composition comprising a compound according to any preceding claim and a
pharmaceutical carrier.
19. A composition in accordance with Claim 18, in the form of a tablet, capsule or elixir for oral
administration or a sterile solution or suspension for parenteral administration.
20. A composition in accordance with Claim 18 or 19 which includes an excipient, binder, preservative, stabiliser or flavor.
21. A compound in accordance with any one of claims 1 to 17 for use in the treatment of hypertension.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4033579A | 1979-05-18 | 1979-05-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2050359A true GB2050359A (en) | 1981-01-07 |
| GB2050359B GB2050359B (en) | 1983-05-18 |
Family
ID=21910442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8014648A Expired GB2050359B (en) | 1979-05-18 | 1980-05-02 | Derivatives of mercaptoacyl amino acids |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5612365A (en) |
| DE (1) | DE3018467A1 (en) |
| FR (2) | FR2468589A1 (en) |
| GB (1) | GB2050359B (en) |
| IE (1) | IE49790B1 (en) |
| IT (1) | IT1140954B (en) |
| ZA (1) | ZA802420B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2479827A1 (en) * | 1980-04-03 | 1981-10-09 | Squibb & Sons Inc | |
| EP0038117A1 (en) * | 1980-03-10 | 1981-10-21 | University Of Miami | Methods for preparing anti-hypertensive agents |
| AT386603B (en) * | 1981-06-19 | 1988-09-26 | Chugai Pharmaceutical Co Ltd | METHOD FOR PRODUCING NEW PROLIN DERIVATIVES |
| AT390619B (en) * | 1981-06-19 | 1990-06-11 | Chugai Pharmaceutical Co Ltd | METHOD FOR PRODUCING NEW PROLIN DERIVATIVES |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5839661A (en) * | 1981-09-03 | 1983-03-08 | Chugai Pharmaceut Co Ltd | Preparation of proline derivative |
| AT377496B (en) * | 1981-06-19 | 1985-03-25 | Voith Gmbh J M | DEVICE FOR WINDING A TRACK OF GOODS ON A NEWLY INSERTED WRAPPING SLEEVE IN A DOUBLE-CARRIER ROLLING MACHINE |
| JPS58131968A (en) * | 1981-09-09 | 1983-08-06 | Chugai Pharmaceut Co Ltd | Thiol ester compound |
| JPS6345252A (en) * | 1987-03-18 | 1988-02-26 | Chugai Pharmaceut Co Ltd | Proline derivative |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1591598A (en) * | 1967-07-31 | 1970-05-04 | ||
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| US4113715A (en) * | 1977-01-17 | 1978-09-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| FR2412537A1 (en) * | 1977-12-22 | 1979-07-20 | Science Union & Cie | NEW SUBSTITUTE THIOBUTYRAMIDES, THEIR METHODS OF OBTAINING AND THEIR PHARMACEUTICAL APPLICATION |
| PH15381A (en) * | 1978-02-21 | 1982-12-17 | Squibb & Sons Inc | Halogen substituted mercaptoacylamino acids |
| GR73585B (en) * | 1978-09-11 | 1984-03-26 | Univ Miami | |
| ZA794723B (en) * | 1978-09-11 | 1980-08-27 | Univ Miami | Anti-hypertensive agents |
-
1980
- 1980-04-22 ZA ZA00802420A patent/ZA802420B/en unknown
- 1980-05-02 GB GB8014648A patent/GB2050359B/en not_active Expired
- 1980-05-07 FR FR8010182A patent/FR2468589A1/en active Granted
- 1980-05-08 IE IE954/80A patent/IE49790B1/en not_active IP Right Cessation
- 1980-05-14 DE DE19803018467 patent/DE3018467A1/en not_active Ceased
- 1980-05-16 IT IT22148/80A patent/IT1140954B/en active
- 1980-05-17 JP JP6584780A patent/JPS5612365A/en active Granted
- 1980-10-07 FR FR8021415A patent/FR2467198A1/en active Granted
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0038117A1 (en) * | 1980-03-10 | 1981-10-21 | University Of Miami | Methods for preparing anti-hypertensive agents |
| FR2479827A1 (en) * | 1980-04-03 | 1981-10-09 | Squibb & Sons Inc | |
| AT386603B (en) * | 1981-06-19 | 1988-09-26 | Chugai Pharmaceutical Co Ltd | METHOD FOR PRODUCING NEW PROLIN DERIVATIVES |
| AT390619B (en) * | 1981-06-19 | 1990-06-11 | Chugai Pharmaceutical Co Ltd | METHOD FOR PRODUCING NEW PROLIN DERIVATIVES |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0135824B2 (en) | 1989-07-27 |
| ZA802420B (en) | 1981-04-29 |
| IE49790B1 (en) | 1985-12-11 |
| DE3018467A1 (en) | 1981-01-22 |
| FR2467198A1 (en) | 1981-04-17 |
| FR2467198B1 (en) | 1983-06-17 |
| JPS5612365A (en) | 1981-02-06 |
| FR2468589A1 (en) | 1981-05-08 |
| IT8022148A0 (en) | 1980-05-16 |
| GB2050359B (en) | 1983-05-18 |
| IE800954L (en) | 1980-11-18 |
| IT1140954B (en) | 1986-10-10 |
| FR2468589B1 (en) | 1983-07-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930502 |