CA2126198A1 - New tetrahydronaphthalene derivatives - Google Patents
New tetrahydronaphthalene derivativesInfo
- Publication number
- CA2126198A1 CA2126198A1 CA002126198A CA2126198A CA2126198A1 CA 2126198 A1 CA2126198 A1 CA 2126198A1 CA 002126198 A CA002126198 A CA 002126198A CA 2126198 A CA2126198 A CA 2126198A CA 2126198 A1 CA2126198 A1 CA 2126198A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- general formula
- tetrahydro
- oxo
- naphthyl
- 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.)
- Abandoned
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to new tetrahydronaphthalene derivatives of general formula (I) wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula -(CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyloxy group or a group of general formula (A), wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, furthermore to a process for preparing the same. The compounds exert valuable antiulcer and cytoprotective activity in mammals including men.
Description
2 1 2 li 1 9 8 PCI/~IIU92/0005~3 NE'W TETRAHYDRONAPHTHALENE DE~IVATIVES
The invention relates to new tetrahydro-naphthalene derivatives of general formula (I) O O
Il 11 11 o ~C--CH=CH-C--N--CH--ICH2)n--C--R3 wherein Rl represents a hydrogen atom, R2 represents a hydrogen atom, a C1_4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-~
R3 represents a hydroxy, C1_4 alkoxy or benzyl-oxy group or a group of general formula (A), ~
--1~ N--COORS
/ (A
wherein RS represents a Cl_4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, further-more to a process for preparing the same.
Compounds of general formula (I) may be in SUBSTITUTE S~tEET
W093/l2070 212 6 19~ 2 - PCT/HU92/0~58 (E) configuration.
In the C1_4 alkyl or C1_4 alkoxy groups the alkyl groups can be linear or branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopro-pyl, furthermore n-, sec- or t-butyl groups.
The new compounds of general formula ~I) proved to be biologically active, they exerted significant antiulcer, i.e. cytoprotective effect.
The invention relates furthermore to pharma-ceutical compositions containing new tetrahydro-naphthalene derivatives of general formula (I) -wherein Rl, R2, R3 and n have the same meaning as above - and their pharmaceutically acceptable salts, furthermore to a process for preparing the same.
lS The therapeutic effect of the compounds of general formula ~I) was studied in the following tests.
Cytoprotective effect in the acidic ~lcohol i~uced g~tric ulcer mo~el (A. Robert: Gastroenterology, 77, 761-767, 1~79) The study was performed in female rats weighing 120 - lS0 g and starved for 24 hours. The test compound was administered in a suspension prepared with Tween 80, by gavage. After 30 minutes acidic alcohol, in doses of 0.5 ml/lO0 g body weight, was added similarly, by gavage. After one hour tbe animals were Xilled, their stomach was removed and cut along the curve. The reddish-brown strips ~hemorrhagic lesions) were measured and their mean length pro stomach was calculated. The protective effect of the test compound was determined compared to the control group. The effect of the compound described in Example 1: ED50- o.l mg/kg p.o.
SUBSTlTUrE SttEET
WO93/12070 2 1~ 8 PCT/HU92/00058 Cytoprotoctive effact in the acetic acid induced chrouic gastric ulcer ~odQl (Tagaki et al: Japanese Journal of Pharmacology 19, 418-426, 1969) The study was performed in female rats starved for 24 hours. The abdominal wall was opened under ether a nesthesis, and 25 ~l of 20 % acetic acid solution was injected in the subserous layer of the glandular part of the stomach, near the pylorus.
Then the abdominal wall was closed and the animals received food and water ad libitum; Treatment was started on the 5th postoperative day and continued with single daily doses for 10 days. The animals were killed on the 15th postoperative day and their stomach was removed. Evaluation was performed by measuring the diameter of the necrotic areas and calculating their surface. The therapeutic effect of the test compound was calculated according to the following formula 0 ulcer surface ~control~ - ulcer surface (test compound) ulcer surface (control) The therapeutic effect of the compound of Example 1 amounted to 39 % at doses of 10 mg/kg p.o.
The pharmacological studies confirmed that the compounds of the present invention as well as their pharmaceutically acceptable salts are potent antiulcer agents.
The invention also relates to a process for preparing new tetràhydronaphthalene derivatives of general formula (I) - wherein R1, R2, R3 and n have the same meaning as above - w h i c h c o m p r i s -e s - reacting an activated derivative of 4-oxo-4-SUBSrlTUTE SHEET
W093~12070 PCT/HU92/00058 ~61S8 - 4 -(5,6,7,8-tetrahydro-2-napthyl)-2(E)- butenoic acid of qeneral formula (II), o ~C- CH=CH--COOH
with an amino acid derivative of general formula (III), NH--CH--ICH2)n--C--R4 Rl R2 ( ~
wherein R1 and R2 have the same meaning as above, and R4 represents a Cl_4 alkoxy or benzyloxy group or a group of formula A - whercin R5 represents a Cl_ alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein Rl and R2 have the same meaning as above and R3 sta~ds for a t-butyloxy group - andJor if desired, reacting an activated derivative of a compound of general formula (I) - wherein R1 and R~ ha~e the same meaning as above and R3 stands for a hydroxy group - with a piperazine derivative contain-SV~E 5~EF~
WO93/12070 ~ 12 6 1 s ~ PCTtHU92/00058 ing a group of formula A - wherein R5 has the same meaning as above - or are converted with an inorganic or organic base to a salt.
From the starting materials applied in the process the compounds of general formula (III) are commercial products.
The 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl-2(E)-butenoic acid of general formula (II) can be prepared from l,2,3,4-tetrahydronaphthalene and maleic anhydride in a Friedel-Krafts reaction according to D.
Papa et al: J. Am. Chem. Soc.: 70, 3356, 1948.
According to a preferred embodiment of the present invention the amide formation between the compounds of general formulas (II) and (III) is performed by activating in situ first 4-oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic a~id of formula (II), and reacting it in an inert organic solvent with the amine component of the formula (III).
The carboxy group of the compound of formula (II) can be activated by not less than stoichio~etric amounts of a carbodiimide type reagent, i. e. dicyclo~exyl-carbodiimide, in an inert organic solvent, preferably in a halogenated aliphatic hydrocarbon, advantageously in dichloromethane, at a preferred temperature range of 0C to 20C. An other preferred type of activation is the mixed anhydride method, wherein a chloroformic acid ester, preferably ethyl chloroformate is applied.
The reaction is performed in an inert organic solvent, i. e. in a cyclic ether, preferably in tetrahydrofu-ran, in the presence of stoichiometric amounts of a t-amine base, preferably in triethylamine, at a preferred temperature ran~e of -20QC to 0C. In the case when a compound of general formula tI)- wherein Rl and R2 have the same meaning as above and R3 is a hydroxy group - is reacted with a piperazine SUBSTITUTE SHEET
WO93/12070 PCTtHU92/00058 2 1 2 61-qg - 6 -deriv ~ ~v~ acid is activated by either of theabove methods, i. e. either by the mixed anhydride or the carbodiimide method.
If desired, the compounds of general formula S (I) - wherein Rl and R2 have the same meaning as above and R3 stands for a hydroxy group - can be converted by known methods with an organic or inorganic base into an alkali metal, alkali earth metal or zinc salt.
The compounds of general formula (I) - wherein Rl, R2 and R3 have the same meaning as above - prepar-ed by the process of the invention, can be isolated by known methods, i. e. filtration, and purified by re-crystallization.
The compounds of the invention can be converted into pharmaceutical formulations suitable for parenteral or enteral administration by mixing them with non-toxic, inert solid or liquid carriers and/or additives. Water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, and plant oils, such as peanut oil, olive oil, etc., can be used as carriers. The active ingredient can be formulated as is usual in pharmaceutical compositions, in solid forms, i.e. round or rectangular tablets, coated tablets, capsules, i. e. gelatine capsules, pills, or suppositories.
The compositions can contain, if required, the usual auxiliary materials, such a~ preservatives, stabilizers, wetting agents, emulsifying agents, etc.
They can be prepared by usual methods, so in the case of solid formulations, by sieving, mixing, granulating and pressing. The formulations can be submitted to the usual pharmaceutical technological procedures, i. e.
sterilization.
The following examples are illustrating but
The invention relates to new tetrahydro-naphthalene derivatives of general formula (I) O O
Il 11 11 o ~C--CH=CH-C--N--CH--ICH2)n--C--R3 wherein Rl represents a hydrogen atom, R2 represents a hydrogen atom, a C1_4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-~
R3 represents a hydroxy, C1_4 alkoxy or benzyl-oxy group or a group of general formula (A), ~
--1~ N--COORS
/ (A
wherein RS represents a Cl_4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, further-more to a process for preparing the same.
Compounds of general formula (I) may be in SUBSTITUTE S~tEET
W093/l2070 212 6 19~ 2 - PCT/HU92/0~58 (E) configuration.
In the C1_4 alkyl or C1_4 alkoxy groups the alkyl groups can be linear or branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopro-pyl, furthermore n-, sec- or t-butyl groups.
The new compounds of general formula ~I) proved to be biologically active, they exerted significant antiulcer, i.e. cytoprotective effect.
The invention relates furthermore to pharma-ceutical compositions containing new tetrahydro-naphthalene derivatives of general formula (I) -wherein Rl, R2, R3 and n have the same meaning as above - and their pharmaceutically acceptable salts, furthermore to a process for preparing the same.
lS The therapeutic effect of the compounds of general formula ~I) was studied in the following tests.
Cytoprotective effect in the acidic ~lcohol i~uced g~tric ulcer mo~el (A. Robert: Gastroenterology, 77, 761-767, 1~79) The study was performed in female rats weighing 120 - lS0 g and starved for 24 hours. The test compound was administered in a suspension prepared with Tween 80, by gavage. After 30 minutes acidic alcohol, in doses of 0.5 ml/lO0 g body weight, was added similarly, by gavage. After one hour tbe animals were Xilled, their stomach was removed and cut along the curve. The reddish-brown strips ~hemorrhagic lesions) were measured and their mean length pro stomach was calculated. The protective effect of the test compound was determined compared to the control group. The effect of the compound described in Example 1: ED50- o.l mg/kg p.o.
SUBSTlTUrE SttEET
WO93/12070 2 1~ 8 PCT/HU92/00058 Cytoprotoctive effact in the acetic acid induced chrouic gastric ulcer ~odQl (Tagaki et al: Japanese Journal of Pharmacology 19, 418-426, 1969) The study was performed in female rats starved for 24 hours. The abdominal wall was opened under ether a nesthesis, and 25 ~l of 20 % acetic acid solution was injected in the subserous layer of the glandular part of the stomach, near the pylorus.
Then the abdominal wall was closed and the animals received food and water ad libitum; Treatment was started on the 5th postoperative day and continued with single daily doses for 10 days. The animals were killed on the 15th postoperative day and their stomach was removed. Evaluation was performed by measuring the diameter of the necrotic areas and calculating their surface. The therapeutic effect of the test compound was calculated according to the following formula 0 ulcer surface ~control~ - ulcer surface (test compound) ulcer surface (control) The therapeutic effect of the compound of Example 1 amounted to 39 % at doses of 10 mg/kg p.o.
The pharmacological studies confirmed that the compounds of the present invention as well as their pharmaceutically acceptable salts are potent antiulcer agents.
The invention also relates to a process for preparing new tetràhydronaphthalene derivatives of general formula (I) - wherein R1, R2, R3 and n have the same meaning as above - w h i c h c o m p r i s -e s - reacting an activated derivative of 4-oxo-4-SUBSrlTUTE SHEET
W093~12070 PCT/HU92/00058 ~61S8 - 4 -(5,6,7,8-tetrahydro-2-napthyl)-2(E)- butenoic acid of qeneral formula (II), o ~C- CH=CH--COOH
with an amino acid derivative of general formula (III), NH--CH--ICH2)n--C--R4 Rl R2 ( ~
wherein R1 and R2 have the same meaning as above, and R4 represents a Cl_4 alkoxy or benzyloxy group or a group of formula A - whercin R5 represents a Cl_ alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein Rl and R2 have the same meaning as above and R3 sta~ds for a t-butyloxy group - andJor if desired, reacting an activated derivative of a compound of general formula (I) - wherein R1 and R~ ha~e the same meaning as above and R3 stands for a hydroxy group - with a piperazine derivative contain-SV~E 5~EF~
WO93/12070 ~ 12 6 1 s ~ PCTtHU92/00058 ing a group of formula A - wherein R5 has the same meaning as above - or are converted with an inorganic or organic base to a salt.
From the starting materials applied in the process the compounds of general formula (III) are commercial products.
The 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl-2(E)-butenoic acid of general formula (II) can be prepared from l,2,3,4-tetrahydronaphthalene and maleic anhydride in a Friedel-Krafts reaction according to D.
Papa et al: J. Am. Chem. Soc.: 70, 3356, 1948.
According to a preferred embodiment of the present invention the amide formation between the compounds of general formulas (II) and (III) is performed by activating in situ first 4-oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic a~id of formula (II), and reacting it in an inert organic solvent with the amine component of the formula (III).
The carboxy group of the compound of formula (II) can be activated by not less than stoichio~etric amounts of a carbodiimide type reagent, i. e. dicyclo~exyl-carbodiimide, in an inert organic solvent, preferably in a halogenated aliphatic hydrocarbon, advantageously in dichloromethane, at a preferred temperature range of 0C to 20C. An other preferred type of activation is the mixed anhydride method, wherein a chloroformic acid ester, preferably ethyl chloroformate is applied.
The reaction is performed in an inert organic solvent, i. e. in a cyclic ether, preferably in tetrahydrofu-ran, in the presence of stoichiometric amounts of a t-amine base, preferably in triethylamine, at a preferred temperature ran~e of -20QC to 0C. In the case when a compound of general formula tI)- wherein Rl and R2 have the same meaning as above and R3 is a hydroxy group - is reacted with a piperazine SUBSTITUTE SHEET
WO93/12070 PCTtHU92/00058 2 1 2 61-qg - 6 -deriv ~ ~v~ acid is activated by either of theabove methods, i. e. either by the mixed anhydride or the carbodiimide method.
If desired, the compounds of general formula S (I) - wherein Rl and R2 have the same meaning as above and R3 stands for a hydroxy group - can be converted by known methods with an organic or inorganic base into an alkali metal, alkali earth metal or zinc salt.
The compounds of general formula (I) - wherein Rl, R2 and R3 have the same meaning as above - prepar-ed by the process of the invention, can be isolated by known methods, i. e. filtration, and purified by re-crystallization.
The compounds of the invention can be converted into pharmaceutical formulations suitable for parenteral or enteral administration by mixing them with non-toxic, inert solid or liquid carriers and/or additives. Water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, and plant oils, such as peanut oil, olive oil, etc., can be used as carriers. The active ingredient can be formulated as is usual in pharmaceutical compositions, in solid forms, i.e. round or rectangular tablets, coated tablets, capsules, i. e. gelatine capsules, pills, or suppositories.
The compositions can contain, if required, the usual auxiliary materials, such a~ preservatives, stabilizers, wetting agents, emulsifying agents, etc.
They can be prepared by usual methods, so in the case of solid formulations, by sieving, mixing, granulating and pressing. The formulations can be submitted to the usual pharmaceutical technological procedures, i. e.
sterilization.
The following examples are illustrating but
3~ not limiting the scope of the invention.
~UBSTITUTE SHEET
W093/l~070 PCT/HU92/00058 _ 7 _ 212~1~8 Exam~le 1
~UBSTITUTE SHEET
W093/l~070 PCT/HU92/00058 _ 7 _ 212~1~8 Exam~le 1
4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L-proline ethyl ester 4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8-tetra-hydro-2-naphthyl-2(E)-butenoic acid are dissolved in 100 ml of anhydrous dichloromethane, then 5.6 ml (0.04 mole) of triethylamine are added. The solution is cooled to -15~C, thereafter 2.01 ml (0.022 mole) of ethyl chloroformate, dissolved in 10 ml of anhydrous dichloromethane, then at -15C 4.0 g (0.022 mole) of L-proline ethyl ester hydrochloride, dissolved in 10 ml of anhydrous dichloromethane are added. The reaction mixture is stirred first at -15C for 30 minutes, then at room temperature for 2 hours, and the mixture is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, 5 %
sodium carbonate and saturated sodium chloride solu- -~
tion. The organic layer is dried over sodium sulfate and evaporated. The evaporation residue is crystallized from a mixture of cyclohexane-petroleum ether (1:1).
Yield: 5.03 g ~70 %) M.p.: 63-66C
[~]D25: -78.8C (c=0.5, chloroform) Exam~le 2 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoyl]-L-proline 7.66 g t0.02 mole) of 4-oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L-proline t-butyl ester are stirred in 200 ml of 2.4 N hydro-chloric acid solution in dioxane for 24 hours, then the mixture is evaporated. The evaporation residue is dissolved in 200 ml of dichloromethane and the SUBSTrTUTE SHEET
WO93/1~070 2 1 ~ 61 3 ~ - 8 - PCr/HU92/00058 solution is extracted with water and saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evapo-rate~, to give an oil.
Yield: 6.50 g (g9 %).
ExamPle 3 N-t4-Oxo-4-~5,6,7,8-tetrahydro-2-naphthyl~
2(E)-butenoyl]-L-proline zinc salt tetrahydrate 6.5 g of N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline, prepared according to the process of Example 2, are dissolved in a mix-ture of 10 ml of water and 2.78 ml (0.02 mole~ of tri-ethylamine, then 1.36 g of zinc chloride in 10 ml of water are added. The precipitated compound is filter-ed, washed with ice-water, ethanol and diethyl ether.
The product has light yellow colour.
Yield: 4.9 g (62 %) M.p.: 122-124C
I~D25 -82.4 (c-1, methanol).
Example 4 N-t4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-D-aspartic acid diethyl ester 4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8--~etrahydro-2-naphthyl-2(E)-butenoic acid are dis-solved in 50 ml of anhydrous tetrahydrofuran, 5~6 ml (0.04 mo~e) of triethylamine are added and the solution is cooled to -10C. To this solution are added slowly 2.01 ml (22 mmole) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran. Thereafter, maintaining the temperature of the reaction mixture at -10C, 4.5 g (0.02 mole) of D-aspartic acid diethyl esther are added in 20 ml of anhydrous dichloromethane solution. The reaction mixture is stirred for 30 SlJBSTlTUTE SHEET
WO93/12070 2 ~ ?. ~ PCT/HU92~00058 _ g _ minutes at 10C, sub~equently for one hour at room temperature, then it is poured on 200 ml of water. The mixture is extracted with dichloromethane. The organic layer is repeatedly extracted with 5 % sodium carbona-
sodium carbonate and saturated sodium chloride solu- -~
tion. The organic layer is dried over sodium sulfate and evaporated. The evaporation residue is crystallized from a mixture of cyclohexane-petroleum ether (1:1).
Yield: 5.03 g ~70 %) M.p.: 63-66C
[~]D25: -78.8C (c=0.5, chloroform) Exam~le 2 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoyl]-L-proline 7.66 g t0.02 mole) of 4-oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L-proline t-butyl ester are stirred in 200 ml of 2.4 N hydro-chloric acid solution in dioxane for 24 hours, then the mixture is evaporated. The evaporation residue is dissolved in 200 ml of dichloromethane and the SUBSTrTUTE SHEET
WO93/1~070 2 1 ~ 61 3 ~ - 8 - PCr/HU92/00058 solution is extracted with water and saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evapo-rate~, to give an oil.
Yield: 6.50 g (g9 %).
ExamPle 3 N-t4-Oxo-4-~5,6,7,8-tetrahydro-2-naphthyl~
2(E)-butenoyl]-L-proline zinc salt tetrahydrate 6.5 g of N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline, prepared according to the process of Example 2, are dissolved in a mix-ture of 10 ml of water and 2.78 ml (0.02 mole~ of tri-ethylamine, then 1.36 g of zinc chloride in 10 ml of water are added. The precipitated compound is filter-ed, washed with ice-water, ethanol and diethyl ether.
The product has light yellow colour.
Yield: 4.9 g (62 %) M.p.: 122-124C
I~D25 -82.4 (c-1, methanol).
Example 4 N-t4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-D-aspartic acid diethyl ester 4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8--~etrahydro-2-naphthyl-2(E)-butenoic acid are dis-solved in 50 ml of anhydrous tetrahydrofuran, 5~6 ml (0.04 mo~e) of triethylamine are added and the solution is cooled to -10C. To this solution are added slowly 2.01 ml (22 mmole) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran. Thereafter, maintaining the temperature of the reaction mixture at -10C, 4.5 g (0.02 mole) of D-aspartic acid diethyl esther are added in 20 ml of anhydrous dichloromethane solution. The reaction mixture is stirred for 30 SlJBSTlTUTE SHEET
WO93/12070 2 ~ ?. ~ PCT/HU92~00058 _ g _ minutes at 10C, sub~equently for one hour at room temperature, then it is poured on 200 ml of water. The mixture is extracted with dichloromethane. The organic layer is repeatedly extracted with 5 % sodium carbona-
5 te and saturated sodium chloride solutions. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. Light yellow crystals are formed from the evaporation residue after adding petroleum ether.
Yield: 5.6 g (70 %) M.p.: 95-97C
t~]D25: -0.33O (~=0.5, chloroform).
Example 5 1-tN-/4-Oxo-4-(5,6~7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl]-4-ethoxycarbonyl-piperazine 4.24 g (18.4 mmole) of 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 80 ml of anhydrous tetrahydrofuran, 2.57 ml (18.4 mmole) of triethylamine are added, then 1.76 --ml (18.4 mmole) of ethyl chloroformate in 10 ml of anhydrous tetrahydrofuran. To this mixture are added 4.7 g of 1-L-prolyl-4-ethoxycarbonylpiperazine -prepared according to paragraph b) of the production process of starting materials - i~ 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at -15~C, then at -10C for 30 minutes and at room temperature for one hour. Subsequently the mixture is poured on 400 ml of water and extra ted with dichloro-methane. The organic layer is extracted first with 5 % sodium carbonate solution, then with water, finally with saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil is ~5 recrystallized from a mixture of diethyl ether and SUBSTITUTE SHEET
W093/12070 PCT~HU92/00058 ~1261.38 - lo-isopropanol.
Yield: 4.87 g (57 %) M . P .: 110-112 C
t~]D25: +9.4O (c=1, chloroform).
ExamPle 6 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-~-proline benzyl ester 14.5 g (0.06 mole) of L-proline benzyl ester hydrochloride and 8.3 g (0.06 mole) of potassium carbonate are dissolved in a mixture of 100 ml of water and 100 ml of dichloromethane. The organic layer is dried and the solvent is evaporated. The residual oil is directly processed in the next step.
13.8 g (0.06 mole) of 4-oxo-4 (5,6,7,8-tetrahydro-2-naphthyl)-2(E)butenoic acid are dissolved in 150 ml of anhydrous tetrahydrofuran and the solution is cooled to -15C. Then 8.4 ml (0.06 mole) of triethylamine and subsequently 6.1 ml (66 mmole~ of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added. Thereafter the solution of L-proline benzyl ester base in 20 ml of anhydrous tetrahydrofuran, obtained in the previous step, is added. The reaction mixture is stirred for 30 minutes at -15C, for a further hour at room temperature, then it is pou~ed on 400 ml of water and extracted with ~ichloromethane. The organic layer is washed first with 5 % sodium carbonate solution, then with water and finally with a saturated sodium chloride solution.
The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from petroleum ether and recrystallized from a mixture of acetone-n-hexan.
Yield: 12.0 g (4~ %).
M.p.: 95-96C.
SUBSrlTUTE SHEET
WO93/12070 2 12 ~ 1 3 8 PCT/HU92/00058 ~]D25: -411 (c-1, chloroform) -~xam~le 7 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-B-alanine ethyl ester 2.3 g (0.01 mole) of 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid and 1.53 g (0.01 mole) of B-alanine ethyl ester hydrochloride are suspended in 50 ml of anhydrous dichloromethane and cooled to 0OC. Then 1.01 g t0.01 mole) of N-methyl-morpholine in 20 ml of anhydrous dichloromethane and finally 2.06 g (0.01 mole3 of dicyclohexylcarbodiimide are added to the suspension. The reaction mixture is stirred for one hour at 0C and for one hour at room temperature.
The precipitated dicyclohexylurea is filtered, and the filtrate is extracted with the following solvents in the order listed: 1 ~
hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of diethyl ether.
Yi~ld: 1.3 g (41 %).
M.p.: 112-114C.
Example 8 N-t4-Oxo-4-(5,6,7,~-tetrahydro-2-naphthyl)-2(E)-butenoyl]-6-aminohexanoic acid ethyl ester 2.3 g (0.01 mole) of 4-oxo-4-(5,6,7,8-- -tetrahydro-2-naphthyl)-2-(E)-butenoic acid and 1.95 g (1.01 mole) of 6-aminohexanoic acid ethyl ester are suspended in 60 ml of anhydrous dichloromethane and cooled to 0C. To this mixture first a solution of 1.01 g (0.01 mole) of N-methylmorpholine in 20 ml ~f SUBSTrrUTE SHEET
2 1 ~ 8 - 12 -anhydrous dichloromethane, then 2.06 g (0.01 mole) of dicyclohexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0C and for one hour at room temperature. The precipitated di-cyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from a mixture of diethyl ether and n-hexane.
Yield~ 8 g (40 %).
M.p.: 74-76OC.
Example 9 N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2( F ) -butenoyl3-L-phenylalanine methyl ester 4.3 g (0.02 mole) of L-phenylalanine methyl ester hydrochloride and 4.6 g (0.02 mole) of 4-oxo-4~
(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid are suspended in 80 ml of anhydrous dichloromethane and cooled to 0C. To this mixture a solution of 2.03 g (0.02 mole) of N-methylmorpholine in 30 ml of an-hydrous dichloromethane, then 4.12 g (0.02 mole) of dicyclo-hexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0C and f or one hour at room temperature. The precipitated dicyclo-hexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N
hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution.
The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The W093/l2070 - 13 - 2 12 6 1~ ~
evaporation residue is crystallized from diethyl ether, and recrystallized from a mixture of ethyl acetate and diethyl ether.
Yield: 3.7 g (47 %).
M.p.: 145-147C.
[~]D25: -22.5 (c=1, methanol).
Example 10 1-[N-/4-Oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl~-4-ethoxycarbonylpiperazine
Yield: 5.6 g (70 %) M.p.: 95-97C
t~]D25: -0.33O (~=0.5, chloroform).
Example 5 1-tN-/4-Oxo-4-(5,6~7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl]-4-ethoxycarbonyl-piperazine 4.24 g (18.4 mmole) of 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 80 ml of anhydrous tetrahydrofuran, 2.57 ml (18.4 mmole) of triethylamine are added, then 1.76 --ml (18.4 mmole) of ethyl chloroformate in 10 ml of anhydrous tetrahydrofuran. To this mixture are added 4.7 g of 1-L-prolyl-4-ethoxycarbonylpiperazine -prepared according to paragraph b) of the production process of starting materials - i~ 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at -15~C, then at -10C for 30 minutes and at room temperature for one hour. Subsequently the mixture is poured on 400 ml of water and extra ted with dichloro-methane. The organic layer is extracted first with 5 % sodium carbonate solution, then with water, finally with saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil is ~5 recrystallized from a mixture of diethyl ether and SUBSTITUTE SHEET
W093/12070 PCT~HU92/00058 ~1261.38 - lo-isopropanol.
Yield: 4.87 g (57 %) M . P .: 110-112 C
t~]D25: +9.4O (c=1, chloroform).
ExamPle 6 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-~-proline benzyl ester 14.5 g (0.06 mole) of L-proline benzyl ester hydrochloride and 8.3 g (0.06 mole) of potassium carbonate are dissolved in a mixture of 100 ml of water and 100 ml of dichloromethane. The organic layer is dried and the solvent is evaporated. The residual oil is directly processed in the next step.
13.8 g (0.06 mole) of 4-oxo-4 (5,6,7,8-tetrahydro-2-naphthyl)-2(E)butenoic acid are dissolved in 150 ml of anhydrous tetrahydrofuran and the solution is cooled to -15C. Then 8.4 ml (0.06 mole) of triethylamine and subsequently 6.1 ml (66 mmole~ of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added. Thereafter the solution of L-proline benzyl ester base in 20 ml of anhydrous tetrahydrofuran, obtained in the previous step, is added. The reaction mixture is stirred for 30 minutes at -15C, for a further hour at room temperature, then it is pou~ed on 400 ml of water and extracted with ~ichloromethane. The organic layer is washed first with 5 % sodium carbonate solution, then with water and finally with a saturated sodium chloride solution.
The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from petroleum ether and recrystallized from a mixture of acetone-n-hexan.
Yield: 12.0 g (4~ %).
M.p.: 95-96C.
SUBSrlTUTE SHEET
WO93/12070 2 12 ~ 1 3 8 PCT/HU92/00058 ~]D25: -411 (c-1, chloroform) -~xam~le 7 N-~4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-B-alanine ethyl ester 2.3 g (0.01 mole) of 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid and 1.53 g (0.01 mole) of B-alanine ethyl ester hydrochloride are suspended in 50 ml of anhydrous dichloromethane and cooled to 0OC. Then 1.01 g t0.01 mole) of N-methyl-morpholine in 20 ml of anhydrous dichloromethane and finally 2.06 g (0.01 mole3 of dicyclohexylcarbodiimide are added to the suspension. The reaction mixture is stirred for one hour at 0C and for one hour at room temperature.
The precipitated dicyclohexylurea is filtered, and the filtrate is extracted with the following solvents in the order listed: 1 ~
hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of diethyl ether.
Yi~ld: 1.3 g (41 %).
M.p.: 112-114C.
Example 8 N-t4-Oxo-4-(5,6,7,~-tetrahydro-2-naphthyl)-2(E)-butenoyl]-6-aminohexanoic acid ethyl ester 2.3 g (0.01 mole) of 4-oxo-4-(5,6,7,8-- -tetrahydro-2-naphthyl)-2-(E)-butenoic acid and 1.95 g (1.01 mole) of 6-aminohexanoic acid ethyl ester are suspended in 60 ml of anhydrous dichloromethane and cooled to 0C. To this mixture first a solution of 1.01 g (0.01 mole) of N-methylmorpholine in 20 ml ~f SUBSTrrUTE SHEET
2 1 ~ 8 - 12 -anhydrous dichloromethane, then 2.06 g (0.01 mole) of dicyclohexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0C and for one hour at room temperature. The precipitated di-cyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from a mixture of diethyl ether and n-hexane.
Yield~ 8 g (40 %).
M.p.: 74-76OC.
Example 9 N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2( F ) -butenoyl3-L-phenylalanine methyl ester 4.3 g (0.02 mole) of L-phenylalanine methyl ester hydrochloride and 4.6 g (0.02 mole) of 4-oxo-4~
(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid are suspended in 80 ml of anhydrous dichloromethane and cooled to 0C. To this mixture a solution of 2.03 g (0.02 mole) of N-methylmorpholine in 30 ml of an-hydrous dichloromethane, then 4.12 g (0.02 mole) of dicyclo-hexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0C and f or one hour at room temperature. The precipitated dicyclo-hexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N
hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution.
The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The W093/l2070 - 13 - 2 12 6 1~ ~
evaporation residue is crystallized from diethyl ether, and recrystallized from a mixture of ethyl acetate and diethyl ether.
Yield: 3.7 g (47 %).
M.p.: 145-147C.
[~]D25: -22.5 (c=1, methanol).
Example 10 1-[N-/4-Oxo-4-~5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl~-4-ethoxycarbonylpiperazine
6.5 g of the oily N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline -prepared according to the process described in Example 2 - are dissolved in 150 ml of anhydrous dichloro- -methane, cooled to OoC, then 3.16 g (0.02 mole) of 1-ethoxycarbonylpiperazine and catalytic amounts of 4-dimethylaminopyridine are added. To this mixture a solution of 4.54 q (22 mmole) of dicyclohexylcarbo-diimide in 20 ml of anhydrous dichloromethane are added under constant stirring. The reaction mixture is stirred for 24 hours at room temperature. The precipi-tated dicyclohexylurea is filtered and washed with with dichloromethane. The organic layer is extracted with the following solu~ions in the order listed: l N
hydrochloric acid, water, 10 ~ sodium carbonate solution, water, and finally saturated ~odiu~ chloride solution. The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated. The resulting oil is recrystallized from a 3iO mixture of diethyl ether and isopropanol.
Yield: 5.1 g (55 ~).
M.p.: 110-112C.
~]D25 ~9.2 (c-l, chloroform).
Pre~aration of startina materials SUE~STIlUTE SHEET
W093/l2070 PCT/HU92/0~58 2 1 ? 6 1 9 8 a.) N-~4-Oxo-4-~S,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoyl]-L-proline t-butyl ester 5.23 g (0.02 mole) of L-proline t-butyl ester oxalate are suspended in 50 ml of dichlorome-thane, and the mixture is extracted with a solution of2.76 g (0.02 mole) of potassium carbonate in S0 ml of water up to the point the solution gets clear. The organic layer is separated, dried over anhydrous sodium sulfate, and evaporated.
Yield: 3.7 g of L-proline t-butyl ester.
4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8-tetra-hydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and 2.8 ml (0.02 lS mole) of triethylamine are added. The reaction mixture is cooled to -15C, then a solution of 2.01 ml (22 mmole) ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added, 2nd thereafter the above prepared solution of 3.7 g (22 mmoie) of L-proline t- -butyl ester in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 minutes at -15C, for 30 minutes at room temperature, then it is poured on 200 ml of water and extracted with dichloromethane.
The organic layer is extracted with the followlng solutions in the order listed: 5 % sodium carbonate solution, saturated sodium chloride solution and finally water. The organic layer is dried over anhydrous magnesium suIfate and the solvent is evaporated. The residue crystallizes upon the addition of petroleum ether.
Yield: 3.89 g t51 %).
M.p.: 9s-98C.
[~D25: -81.2 (c=0.5, chloroform).
b) 1-(N-8enzyloxycarbonyl-L-prolyl)-4-ethoxycarbonyl-SUBSrlTUTE SHEET
WO93/12070 - 15 - ~ 1 2 61 ~ 8 pipera z ine 12.45 g (0.05 mole) of N-benzyloxycarbonyl-L-proline and 7.91 g (O.05 mole) of 1 ethoxycarbonyl-piperazine are dissolved in 150 ml of anhydrous dichloromethane, cooled to +5C, then a solution of 11.35 g (55 mmole) of dicyclohexylcarbodiimide in 50 ml of anhydrous dichloromethane are added. The mixture is stirred for 24 hours at room temperature, the precipitated dicyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, lO %
sodium carbonate solution, and finally water. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The product starts to crystallize upon refrigerating. The white crystals are filtered and washed with cool diethyl ether.
Yield: 14.0 g (72 %).
M.p.: 90.5-92C.
t~]D30: -11.4 (c=1, methanol).
c) l-L-Prolyl-4-ethoxycarbonylpiperazine
hydrochloric acid, water, 10 ~ sodium carbonate solution, water, and finally saturated ~odiu~ chloride solution. The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated. The resulting oil is recrystallized from a 3iO mixture of diethyl ether and isopropanol.
Yield: 5.1 g (55 ~).
M.p.: 110-112C.
~]D25 ~9.2 (c-l, chloroform).
Pre~aration of startina materials SUE~STIlUTE SHEET
W093/l2070 PCT/HU92/0~58 2 1 ? 6 1 9 8 a.) N-~4-Oxo-4-~S,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoyl]-L-proline t-butyl ester 5.23 g (0.02 mole) of L-proline t-butyl ester oxalate are suspended in 50 ml of dichlorome-thane, and the mixture is extracted with a solution of2.76 g (0.02 mole) of potassium carbonate in S0 ml of water up to the point the solution gets clear. The organic layer is separated, dried over anhydrous sodium sulfate, and evaporated.
Yield: 3.7 g of L-proline t-butyl ester.
4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8-tetra-hydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and 2.8 ml (0.02 lS mole) of triethylamine are added. The reaction mixture is cooled to -15C, then a solution of 2.01 ml (22 mmole) ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added, 2nd thereafter the above prepared solution of 3.7 g (22 mmoie) of L-proline t- -butyl ester in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 minutes at -15C, for 30 minutes at room temperature, then it is poured on 200 ml of water and extracted with dichloromethane.
The organic layer is extracted with the followlng solutions in the order listed: 5 % sodium carbonate solution, saturated sodium chloride solution and finally water. The organic layer is dried over anhydrous magnesium suIfate and the solvent is evaporated. The residue crystallizes upon the addition of petroleum ether.
Yield: 3.89 g t51 %).
M.p.: 9s-98C.
[~D25: -81.2 (c=0.5, chloroform).
b) 1-(N-8enzyloxycarbonyl-L-prolyl)-4-ethoxycarbonyl-SUBSrlTUTE SHEET
WO93/12070 - 15 - ~ 1 2 61 ~ 8 pipera z ine 12.45 g (0.05 mole) of N-benzyloxycarbonyl-L-proline and 7.91 g (O.05 mole) of 1 ethoxycarbonyl-piperazine are dissolved in 150 ml of anhydrous dichloromethane, cooled to +5C, then a solution of 11.35 g (55 mmole) of dicyclohexylcarbodiimide in 50 ml of anhydrous dichloromethane are added. The mixture is stirred for 24 hours at room temperature, the precipitated dicyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, lO %
sodium carbonate solution, and finally water. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The product starts to crystallize upon refrigerating. The white crystals are filtered and washed with cool diethyl ether.
Yield: 14.0 g (72 %).
M.p.: 90.5-92C.
t~]D30: -11.4 (c=1, methanol).
c) l-L-Prolyl-4-ethoxycarbonylpiperazine
7.4 g (19 mmole) of l-(N-benzyloxycarbonyl-L-prolyl)-4-ethoxycarbonylpiperazine - prepared above - are dissolved in 150 ml of anhydrous methanol and the solution is submitted to hydrogenation for 2 hours in the presence of a Pd-C catalyst. The solution is evaporated after the removal of the catalyst.
Yield: 4.7 g (96.~ %).
SUBSTITUTE SltEET
Yield: 4.7 g (96.~ %).
SUBSTITUTE SltEET
Claims (9)
1. New tetrahydronaphthalene derivatives of general formula (I), , (I) wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula -(CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyl-oxy group or a group of general formula (A), (A) wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts.
2. Compounds selected from the compounds of general formula (I) as claimed in claim 1:
4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L-proline ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline zinc salt tetrahydrate, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-D-aspartic acid diethyl ester, 1-[N-/4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl]-4-ethoxycarbonylpiperazine, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline benzyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-.beta.-alanine ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-6-aminohexanoic acid ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-phenylalanine methyl ester.
4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L-proline ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline zinc salt tetrahydrate, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-D-aspartic acid diethyl ester, 1-[N-/4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl/-L-prolyl]-4-ethoxycarbonylpiperazine, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline benzyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-.beta.-alanine ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-6-aminohexanoic acid ethyl ester, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-phenylalanine methyl ester.
3. Pharmaceutical composition w h i c h c o m p r i s e s as active ingredient a new tetrahydronaphthalene derivative of general formula (I), wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyl-oxy group or a group of general formula (A), wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and a pharmaceutically acceptable salt thereof as defined in claim 1, in admixture with pharmaceutically acceptable carriers and/or additives.
4. Method for treating mammals (including human beings) suffering from various inflammations and ulcers of the trachea, stomach and duodenum and/or for prophylactic purposes, w h i c h c o m p r i s e s administering a therapeutically effective dose or doses of a new tetrahydronaphthalene derivative of general formula (I), wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyl-oxy group or a group of the general formula (A), wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts as defined in claim 1, in the form of a pure substance or as a pharmaceutical composition containing it as active ingredient.
5. Process for preparing new tetrahydro-naphthalene derivatives of general formula (I), (I) wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyl-oxy group or a group of general formula (A), (A) wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, w h i c h c o m p r i s e s reacting an activated derivative of 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid of general formula (II), (II) with an amino acid derivative of general formula (III), (III) wherein R1 and R2 have the same meaning as above, and R4 represents a C1-4 alkoxy or benzyloxy group or a group of formula A - wherein R5 represents a C1-4 alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein R1 and R2 have the same meaning as above and R3 stands for a t-butyloxy group, and/or if desired, reacting an activated derivative of a compound of the general formula (I) - wherein R1 and R2 have the same meaning as above and R3 stands for a hydroxy group - with a piperazine derivative containing a group of formula A - wherein R5 has the same meaning as above - or are converted with an inorganic or organic base to a salt.
6. Process as claimed in claim 5, w h i c h c o m p r i s e s activating the carbonic acid in situ preferably by a carbodiimide type reagent or by the mixed anhydride method.
7. Process as claimed in claim 5, w h i c h c o m p r i s e s applying 1-etoxycarbonylpiperazine as the piperazine derivative.
8. Process as claimed in claim 5, w h i c h c o m p r i s e s converting the carboxylic acid into an alkali metal, alkali earth metal or zinc salt.
9. Process for preparing pharmaceutical compositions, w h i c h c o m p r i s e s mixing a new tetrahydronaphthalene derivative of the general formula (I), wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C1-4 alkoxycarbonylalkyl or benzyl group, or R1 and R2 together represent a group of formula - (CH2)3-, R3 represents a hydroxy, C1-4 alkoxy or benzyl-oxy group, or a group of the general formula (A), wherein R5 represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, or its pharmaceutically acceptable salt with pharmaceutically acceptable carriers and/or additives and transforming it into a pharmaceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU4021/91 | 1991-12-19 | ||
| HU914021A HU209487B (en) | 1991-12-19 | 1991-12-19 | Process for producing tetrahydro-naphtaline derivatives and pharmaceutical compositions containing them as active agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2126198A1 true CA2126198A1 (en) | 1993-06-24 |
Family
ID=10966554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002126198A Abandoned CA2126198A1 (en) | 1991-12-19 | 1992-12-18 | New tetrahydronaphthalene derivatives |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0618894A1 (en) |
| JP (1) | JPH07502039A (en) |
| CN (1) | CN1074213A (en) |
| CA (1) | CA2126198A1 (en) |
| FI (1) | FI942927A (en) |
| HU (1) | HU209487B (en) |
| IL (1) | IL104196A0 (en) |
| NO (1) | NO942306D0 (en) |
| NZ (1) | NZ245534A (en) |
| TW (1) | TW223623B (en) |
| WO (1) | WO1993012070A1 (en) |
| ZA (1) | ZA929913B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE708617A (en) * | 1966-12-30 | 1968-06-28 | ||
| HU198294B (en) * | 1987-06-10 | 1989-09-28 | Richter Gedeon Vegyeszet | Process for producing butenoic acid amides and pharmaceutical compositions comprising such active ingredient |
| HU198446B (en) * | 1987-09-25 | 1989-10-30 | Richter Gedeon Vegyeszet | Process for production of new amids of buten acid and medical compositions containing such active substances |
-
1991
- 1991-12-19 HU HU914021A patent/HU209487B/en unknown
-
1992
- 1992-12-18 JP JP5510766A patent/JPH07502039A/en active Pending
- 1992-12-18 EP EP93901878A patent/EP0618894A1/en not_active Withdrawn
- 1992-12-18 CA CA002126198A patent/CA2126198A1/en not_active Abandoned
- 1992-12-18 WO PCT/HU1992/000058 patent/WO1993012070A1/en not_active Application Discontinuation
- 1992-12-18 NZ NZ245534A patent/NZ245534A/en unknown
- 1992-12-19 CN CN92113838A patent/CN1074213A/en active Pending
- 1992-12-20 IL IL104196A patent/IL104196A0/en unknown
- 1992-12-21 ZA ZA929913A patent/ZA929913B/en unknown
- 1992-12-21 TW TW081110291A patent/TW223623B/zh active
-
1994
- 1994-06-17 FI FI942927A patent/FI942927A/en not_active Application Discontinuation
- 1994-06-17 NO NO942306A patent/NO942306D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU209487B (en) | 1994-06-28 |
| FI942927A0 (en) | 1994-06-17 |
| EP0618894A1 (en) | 1994-10-12 |
| JPH07502039A (en) | 1995-03-02 |
| IL104196A0 (en) | 1993-05-13 |
| CN1074213A (en) | 1993-07-14 |
| NO942306L (en) | 1994-06-17 |
| TW223623B (en) | 1994-05-11 |
| WO1993012070A1 (en) | 1993-06-24 |
| NO942306D0 (en) | 1994-06-17 |
| HUT63147A (en) | 1993-07-28 |
| FI942927A (en) | 1994-06-17 |
| NZ245534A (en) | 1995-07-26 |
| HU914021D0 (en) | 1992-03-30 |
| ZA929913B (en) | 1993-06-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |