CA1109475A - Thiopropanoylamino acid derivatives - Google Patents
Thiopropanoylamino acid derivativesInfo
- Publication number
- CA1109475A CA1109475A CA330,234A CA330234A CA1109475A CA 1109475 A CA1109475 A CA 1109475A CA 330234 A CA330234 A CA 330234A CA 1109475 A CA1109475 A CA 1109475A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- hydrogen
- compound
- lower alkyl
- benzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000002253 acid Substances 0.000 title abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 8
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 7
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- -1 e.g. Chemical group 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229960002429 proline Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract THIOPROPANOYLAMINO ACID DERIVATIVES
New thiopropanoylamino acid derivatives which have the formula wherein R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl;
are useful as hypotensive agents.
New thiopropanoylamino acid derivatives which have the formula wherein R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl;
are useful as hypotensive agents.
Description
~10~47~ HAl47b THIOPROPANOYLAMINO ACID DERIVATIVES
This invention relates to new thiopropanoylamino acid derivatives which have the formula (I) R
13 ~
In formula I and throughout this specification the symbols have the meanings described below.
R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and the like. The Cl-C4 and especially Cl-C2 alkyl groups are preferred.
The lower alkanoyl groups are the acyl radicals of the lower (C2-C7) fatty acids, e.g., acetyl, propionyl, butyryl, isobutyryl and the like. The members mentioned, and especially acetyl, are preferred.
The compounds of formula I are produced from amino acid compounds having the formula (II) HN - C - COOH
R
by reacting such an acid with a halopropanoyl halide - HA147b having the formula (III) X--CH -C CO-X
wherein each X is halogen, preferably chlorine or bromine, to obtain an intermediate having the formula (IV) 13 ~
X-CH2-f - CO-N f ----COOH
Treatment of this intermediate with a mercaptan (V) (wherein R4 is other than hydrogen) 20 yields a product having the formula (VI )R
R4-S-CH2-C co ~ f COOH
R4 in this instance is other than hydrogen, i.e., the acyl groups lower alkanoyl or benzoyl. By treating the acyl derivative of formula IV with ammonia or concentrated ammonium hydroxide, a compound of formula VI wherein R4 is hydrogen is derived.
11~19475 HA147b Alternatively, by treating the intermediate of formula IV with an alkali metal bisulfide like sodium bisulfide, a product of formula VI wherein R4 is hydrogen is directly obtained.
Additional experimental details can be found in the illustrative examples below.
The compounds of this invention are angiotensin converting enzyme inhibitors and are useful as hypo-tensive agents, particularly for the reduction of angiotensin dependent hypertension. By administering a composition containing one or a combination of angiotensin converting enzyme inhibitor of this invention to a hypertensive mammal, it intervenes in the angiotensinogen ~ trenin) ~ angiotensin I
angiotensin II sequence and the hypertension is reduced or alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 1 to 1000 mg.
per kilogram per day and especially about 10 to 200 mg. per kilogram per day is appropriate to bring about a reduction in elevated blood pressure. The animal model experiments described by Engel et al., Proc.
Soc. Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.
The composition is preferably administered orally, but it can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally.
The compound or compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for patenteral use.
,: - " ~ ' ' ' ,:
11~947,5 HA147b About 50 to 1500 mg. of a compound or compounds of formula I can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, pre-servative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceu-tical practice. The amount of active substance is selected so as to provide a dosage in the range indicated.
The following examples are illustrative of the invention and represent preferred embodiments.
All temperatures are in degrees Celsius.
Example 1 1-(3-Mercapto-2,2-dimethyl-1-oxopropyl-L-proline a) 1-(3-Chloro-2,2-dimethyl-1-oxopropyl)-L-proline L-proline (1.15 g.) is dissolved in 11.8 ml.
of 0.85 N sodium hydroxide with vigorous stirring in an ice-bath. To this solution 5 ml. of 2N sodium hydroxide is added, followed immediately by ~-chloro-pivalic acid chloride and 2 ml. of ether. After 3.5hours, the ninhydrin test is almost negative. To this reaction mixture 12.9 ml. of 0.85 N sodium hydroxide and 820 mg. of thiolacetic acid are added and stirred overnight at room temperature. This is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This material is dissolved in a mixture of ether-hexane (1:10) and the crystalline product that separates (0.4 g., m.p. 116-118, tlc identical to mother liquors) is filtered and the filtrate is concentrated to dryness in vacuo and ; utilized without further purification.
~10547S
HA147b b) l-(3-Mercapto-2,2-dimethyl-l-oxopropyl)-L-proline The R-chloropivaloyl proline from part a (1.15 g.) is dissolved in 5 ml. of water and 920 mg. of sodium bisulfide-H2O under a continuous stream of nitrogen.
The mixture is heated on the steam cone for one hour, acidified with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.1 g. The product is purified by silica gel chromatography with benzene-acetic acid (7:1). The product 1-(3-mercapto-2,2-dimethyl-1-oxopropyl)-L-proline is then crystallized from ethyl acetate and hexane, yield 180 mg., m.p. 94-96.
This invention relates to new thiopropanoylamino acid derivatives which have the formula (I) R
13 ~
In formula I and throughout this specification the symbols have the meanings described below.
R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and the like. The Cl-C4 and especially Cl-C2 alkyl groups are preferred.
The lower alkanoyl groups are the acyl radicals of the lower (C2-C7) fatty acids, e.g., acetyl, propionyl, butyryl, isobutyryl and the like. The members mentioned, and especially acetyl, are preferred.
The compounds of formula I are produced from amino acid compounds having the formula (II) HN - C - COOH
R
by reacting such an acid with a halopropanoyl halide - HA147b having the formula (III) X--CH -C CO-X
wherein each X is halogen, preferably chlorine or bromine, to obtain an intermediate having the formula (IV) 13 ~
X-CH2-f - CO-N f ----COOH
Treatment of this intermediate with a mercaptan (V) (wherein R4 is other than hydrogen) 20 yields a product having the formula (VI )R
R4-S-CH2-C co ~ f COOH
R4 in this instance is other than hydrogen, i.e., the acyl groups lower alkanoyl or benzoyl. By treating the acyl derivative of formula IV with ammonia or concentrated ammonium hydroxide, a compound of formula VI wherein R4 is hydrogen is derived.
11~19475 HA147b Alternatively, by treating the intermediate of formula IV with an alkali metal bisulfide like sodium bisulfide, a product of formula VI wherein R4 is hydrogen is directly obtained.
Additional experimental details can be found in the illustrative examples below.
The compounds of this invention are angiotensin converting enzyme inhibitors and are useful as hypo-tensive agents, particularly for the reduction of angiotensin dependent hypertension. By administering a composition containing one or a combination of angiotensin converting enzyme inhibitor of this invention to a hypertensive mammal, it intervenes in the angiotensinogen ~ trenin) ~ angiotensin I
angiotensin II sequence and the hypertension is reduced or alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 1 to 1000 mg.
per kilogram per day and especially about 10 to 200 mg. per kilogram per day is appropriate to bring about a reduction in elevated blood pressure. The animal model experiments described by Engel et al., Proc.
Soc. Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.
The composition is preferably administered orally, but it can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally.
The compound or compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for patenteral use.
,: - " ~ ' ' ' ,:
11~947,5 HA147b About 50 to 1500 mg. of a compound or compounds of formula I can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, pre-servative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceu-tical practice. The amount of active substance is selected so as to provide a dosage in the range indicated.
The following examples are illustrative of the invention and represent preferred embodiments.
All temperatures are in degrees Celsius.
Example 1 1-(3-Mercapto-2,2-dimethyl-1-oxopropyl-L-proline a) 1-(3-Chloro-2,2-dimethyl-1-oxopropyl)-L-proline L-proline (1.15 g.) is dissolved in 11.8 ml.
of 0.85 N sodium hydroxide with vigorous stirring in an ice-bath. To this solution 5 ml. of 2N sodium hydroxide is added, followed immediately by ~-chloro-pivalic acid chloride and 2 ml. of ether. After 3.5hours, the ninhydrin test is almost negative. To this reaction mixture 12.9 ml. of 0.85 N sodium hydroxide and 820 mg. of thiolacetic acid are added and stirred overnight at room temperature. This is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This material is dissolved in a mixture of ether-hexane (1:10) and the crystalline product that separates (0.4 g., m.p. 116-118, tlc identical to mother liquors) is filtered and the filtrate is concentrated to dryness in vacuo and ; utilized without further purification.
~10547S
HA147b b) l-(3-Mercapto-2,2-dimethyl-l-oxopropyl)-L-proline The R-chloropivaloyl proline from part a (1.15 g.) is dissolved in 5 ml. of water and 920 mg. of sodium bisulfide-H2O under a continuous stream of nitrogen.
The mixture is heated on the steam cone for one hour, acidified with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.1 g. The product is purified by silica gel chromatography with benzene-acetic acid (7:1). The product 1-(3-mercapto-2,2-dimethyl-1-oxopropyl)-L-proline is then crystallized from ethyl acetate and hexane, yield 180 mg., m.p. 94-96.
Claims (8)
1. A process for preparing a compound having the formula:
I wherein R3 and R5 each is lower alkyl; R is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl which com-prises either a) reacting a compound having the formula IV wherein X is halogen, with a compound having the formula wherein R4 is lower alkanoyl or benzoyl to obtain a compound of formula I wherein R4 is lower alkanoyl or benzoyl and R, R3 and R5 have the meaning defined above; or b) treating a compound of formula I wherein R4 is lower alkanoyl or benzoyl with ammonia or concentrated ammonium hydroxide to obtain a compound of formula I wherein R4 is hydrogen and R, R3 and R5 have the meaning defined above; or c) reacting a compound of formula IV with an alkali metal busulfide to obtain a compound of formula I wherein R4 is hydrogen and R, R3 and R5 have the meaning defined above.
I wherein R3 and R5 each is lower alkyl; R is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl which com-prises either a) reacting a compound having the formula IV wherein X is halogen, with a compound having the formula wherein R4 is lower alkanoyl or benzoyl to obtain a compound of formula I wherein R4 is lower alkanoyl or benzoyl and R, R3 and R5 have the meaning defined above; or b) treating a compound of formula I wherein R4 is lower alkanoyl or benzoyl with ammonia or concentrated ammonium hydroxide to obtain a compound of formula I wherein R4 is hydrogen and R, R3 and R5 have the meaning defined above; or c) reacting a compound of formula IV with an alkali metal busulfide to obtain a compound of formula I wherein R4 is hydrogen and R, R3 and R5 have the meaning defined above.
2. The process as in claim 1 wherein R4 is acetyl.
3. The process as in claim 1 wherein R and R4 each is hydrogen and R3 and R5 each is lower alkyl.
4. The process as in claim 1 wherein R and R4 each is hydrogen and R3 and R5 each is lower alkyl.
5. A compound of the formula I wherein R3 and R5 each is lower alkyl; R is hydrogen or lower alkyl; and R4 is hydrogen, lower alkanoyl or benzoyl when prepared by the process of claim 1.
6. A compound as in claim 5 wherein R4 is acetyl when prepared by the process of claim 2.
7. A compound as in claim 5 wherein R and R4 each is hydrogen and R3 and R5 each is lower alkyl when prepared by the process of claim 3.
8. A compound as in claim 5 wherein each lower alkyl group is methyl and R and R4 each is hydrogen when prepared by the process of claim 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92834478A | 1978-07-27 | 1978-07-27 | |
| US928,344 | 1978-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1109475A true CA1109475A (en) | 1981-09-22 |
Family
ID=25456116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA330,234A Expired CA1109475A (en) | 1978-07-27 | 1979-06-21 | Thiopropanoylamino acid derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5520795A (en) |
| CA (1) | CA1109475A (en) |
| DE (1) | DE2930605A1 (en) |
| FR (1) | FR2432019A1 (en) |
| GB (1) | GB2026485B (en) |
| IT (1) | IT1122310B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE50839B1 (en) * | 1980-02-26 | 1986-07-23 | Wyeth John & Brother Ltd | Novel processes for preparing proline derivatives and analogous compounds |
| DE3011239A1 (en) * | 1980-03-22 | 1981-10-01 | C.H. Boehringer Sohn, 6507 Ingelheim | SUBSTITUTED ALKYLTHIOACYLAMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS |
| US4316905A (en) * | 1980-07-01 | 1982-02-23 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of various 4-substituted prolines |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509899B2 (en) * | 1976-02-13 | 1980-05-29 | E.R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| FR2412537A1 (en) * | 1977-12-22 | 1979-07-20 | Science Union & Cie | NEW SUBSTITUTE THIOBUTYRAMIDES, THEIR METHODS OF OBTAINING AND THEIR PHARMACEUTICAL APPLICATION |
-
1979
- 1979-06-21 CA CA330,234A patent/CA1109475A/en not_active Expired
- 1979-06-29 FR FR7917061A patent/FR2432019A1/en not_active Withdrawn
- 1979-07-19 GB GB7925259A patent/GB2026485B/en not_active Expired
- 1979-07-24 IT IT24614/79A patent/IT1122310B/en active
- 1979-07-27 JP JP9664179A patent/JPS5520795A/en active Pending
- 1979-07-27 DE DE19792930605 patent/DE2930605A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| IT1122310B (en) | 1986-04-23 |
| GB2026485B (en) | 1982-10-13 |
| JPS5520795A (en) | 1980-02-14 |
| GB2026485A (en) | 1980-02-06 |
| FR2432019A1 (en) | 1980-02-22 |
| IT7924614A0 (en) | 1979-07-24 |
| DE2930605A1 (en) | 1980-02-07 |
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