Claims
- 1. A compound of formula I ##STR57## wherein: R.sub.1 is a group of formula CO.sub.2 R.sub.5 :
- R.sub.2 is a phenyl ring unsubstituted or substituted with a member selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halo-C.sub.1 -C.sub.4 alkoxy, halo-C.sub.1 -C.sub.6 alkyl, halogen, nitro, cyano, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulphinyl; or R.sub.2 is pentafluorophenyl;
- R.sub.3 is a group of formula CO.sub.2 R.sub.5 ;
- R.sub.4 is
- a C.sub.2 -C.sub.12 alkyl group unsubstituted of substituted by two dissimilar substituents selected from the group consisting of:
- hydroxy;
- thio;
- cyano;
- halogen;
- amino;
- monobenzylamino;
- benzyl(C.sub.1 -C.sub.2)alkylamino;
- C.sub.1 -C.sub.4 alkoxy;
- C.sub.1 -C.sub.4 alkylthio;
- C.sub.1 -C.sub.4 acyloxy;
- C.sub.1 -C.sub.4 acylthio;
- CO.sub.2 H;
- C.sub.1 -C.sub.4 alkoxycarbonyl;
- CONR.sub.6 R.sub.7 ;
- a C.sub.3 -C.sub.7 cycloalkyl;
- n is 0, 1 or 2;
- R.sub.5 is hydrogen, a cation of ammonium or of an alkaline metal; a C.sub.1 -C.sub.6 alkyl chain unsubstituted or substituted by hydroxy, amino, mono(C.sub.1 -C.sub.3)alkylamino, benzylamino, di(C.sub.1 -C.sub.2)alkylamino, benzyl(C.sub.1 -C.sub.2)alkylamino, C.sub.1 -C.sub.6 alkoxy; or C.sub.3 -C.sub.6 alkenyl;
- each of R.sub.6 and R.sub.7, which are the same or different, may be hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl or phenyl;
- or a pharmaceutically acceptable salt thereof.
- 2. A compound according to claim 1, wherein n is zero.
- 3. A compound according to claim 2, wherein R.sub.1 and R.sub.3 are (loweralkoxy) carbonyl groups.
- 4. A compound selected from the group consisting of
- 2-[2-oxopentyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-carboethoxy-2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2-phenyl-2-oxoethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-phenyl-2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethyl-phenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(5-acetylamino-2-oxopentyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(6-acetylamino-2-oxohexyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2,2-diethoxyethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2,2-dimethoxyethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(formylmethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(glutathione-S-yl)thio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, 2-[(glutathione-S-yl-diethylester)thio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2-carbomethoxy-2-aminoethyl)thio]methyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-amino-2-hydroxypropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- [ (3-hydroxy-2-amino-propyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-oxo-1-phenylpropyl)thio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-oxo-cyclohexane-1-yl)thio]methyl-3,5-carboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, or a pharmaceutically acceptable salt thereof.
- 5. A pharmaceutical composition for treating hypertensive conditions or for inducing an antithrombotic, cytoprotective or antiulcer condition, said composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
- 6. A method of producing an antihypertensive condition in a patient in need of such condition, said method comprising administering to said patient an antihypertensive effective amount of a compound of claim 1.
- 7. A compound according to claim 1, wherein said compound is selected from the group consisting of:
- 2-[(formylmethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2-carbomethoxy-2-aminoethyl)thio]methyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-amino-2-hydroxpropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-hydroxy-2-amino-propyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2-amino-2-phenylethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine fumarate,
- and a pharmaceutically acceptable salt thereof.
- 8. A compound selected from the group consisting of:
- 2-[2-oxopentyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-carboethoxy-2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(2-phenyl-2-oxoethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(3-phenyl-2-oxopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethyl-phenyl)-6-methyl-1,4-dihydropyridine,
- 2-[(5-acetylamino-2-oxopentyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, and
- 2-[(6-acetylamino-2-oxohexyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 21876 A/85 |
Aug 1985 |
ITX |
|
| 20965 A/86 |
Jun 1986 |
ITX |
|
| 20966 A/86 |
Jun 1986 |
ITX |
|
Parent Case Info
This is a division of application Ser. No. 889,379, filed July 25, 1986.
The present invention relates to 2-thiomethyl-substituted-1,4-dihydropyridines, to a method for their preparation and to pharmaceutical composition containing them.
The compounds of the invention have the following formula I ##STR2## wherein: R.sub.1 represents acetyl, benzoyl, cyano, nitro groups, or groups of formula CO.sub.2 R.sub.5 or CONR.sub.6 R.sub.7 ;
Also the pharmaceutically acceptable salts as well as the optical antipodes, i.e. the enantiomers, the possible geometric isomers, diastereoisomers and mixtures thereof are included in the scope of the present invention.
The alkyl, alkenyl, alkoxy and alkanoyloxy groups are branched or straight chain groups.
A halo-C.sub.1 -C.sub.6 alkyl group is preferably trihalo-C.sub.1 -C.sub.6 alkyl, in particular trifluoromethyl.
A halo-C.sub.1 -C.sub.4 alkoxy group is preferably --OCHF.sub.2.
A C.sub.1 -C.sub.6 alkyl group is preferably methyl, ethyl, isopropyl or t-butyl.
A C.sub.2 -C.sub.12 alkanoyl group is preferably acetyl, propionyl, hexanoyl or heptanoyl.
An aryl group is preferably phenyl.
A C.sub.3 -C.sub.5 alkenyl group is preferably allyl.
A C.sub.3 -C.sub.5 alkynyl group is preferably propargyl.
A C.sub.3 -C.sub.7 cycloaliphatic radical is preferably cyclopentyl, cyclohexyl and cycloheptyl.
A monoalkyl amino group is preferably a methyl-, ethyl-, isopropyl- or benzyl-amino group.
A dialkylamino group is preferably a linear group such as dimethyl-, diethyl-, benzyl-, methyl-amino group; or a cyclic group such as pyrrolidine-1-yl;piperidine-1-yl, morpholin-1-yl, 4-methyl-piperazine-1-yl, 4-phenyl-pi-perazine-1-yl-4-diphenylmethane-piperazine-1-yl, 4-bis-(p-fluorophenyl)methane-piperazine-1-yl, 4-ethyl-piperazine-1-yl, 4-(2'-hydroxyethyl)piperazine-1-yl.
A C.sub.1 -C.sub.4 alkoxycarbonyl is preferably methoxy-, ethoxy- and ter-butoxy-carbonyl group.
A C.sub.1 -C.sub.3 alkoxy is preferably methoxy and isopropoxy.
A C.sub.1 -C.sub.3 alkylthio is preferably methylthio and isopropylthio.
A masked carbonyl function is preferably an acetal of formula >C(O--C.sub.1-3 alkyl) and more preferably a 1,3-dioxolane or 1,3-dioxane ring wherein one or both the oxygen atoms may be optionally substituted by sulphur atoms.
When R.sub.2 is a five- or six- membered heterocyclic ring, it is preferably pyridyl, furanyl or thienyl; when R.sub.4 is an heterocyclic ring, it may be either a heteromonocyclic ring or a heterobicyclic ring containing at least one heteroatom selected from the group consisting of N, S, and O.
Examples of preferred heteromonocyclic residues are .alpha., .beta., and .gamma.-pyridyl; tetrahydrofuryl; thienyl; .alpha.-pyridyl-N-oxide; 3-hydroxy-.alpha.-pyridyl; 2 and 4-pyrimidinyl; 1H-1,2,4-triazol-3-yl; 1H-1,2,4-triazol-4-yl; 2-thiazolyl; 1-methyl-tetrazol-5-yl; 2-methyl-1,3,4-thiadiazol-5-yl; 5-amino-1,3,4-thiadiazol-2-yl; 2-amino-1,2,4-triazol-5-yl; 2-hydantoinyl; 2-imidazolinyl; 4-methyl-5-trifluoromethyl-4H-1,2,4-triazolin-3-yl; 1-methyl-imidazol-2-yl; 1-phenyl-1H-tetrazol-5-yl; 4,5-diphenyl-4-oxazolyn-2-yl; 5,5-disubstituted-hydantoin-2-yl; 4-phenoxymethyl-5-carboxy-imidazol-2-yl and esters thereof with C.sub.1 -C.sub.4 lower alcohols; 1,4,5,6-tetrahydro-pyrimidin-2-yl;4-substituted-imidazol-2-yl; 5-carboxy-4-substituted-imidazol-2-yl; pyrimidin-2-yl and derivatives thereof with methyl, amino, oxo and/or carboxy groups in 4 and 6 positions of the pyrimidine ring; pyrimidin-4-yl; pyrimidin-6-yl; 2,6-diamino-pyrimidin-4-yl; tetrahydropyran-2-yl; (3,4,5-triacetoxy-6-acetoxymethyl)tetrahydropyran-2-yl; 5-carboethoxy-4-oxo-pyrimidine- 2-yl; 6-propyl-4-hydroxy-pyrimidin-2-yl and 6-propyl-4-amino-pyrimidin-2-yl.
Examples of preferred heterobicyclic residues are: 4-(3H)-quinazolin-4-one-2-yl; quinazolinyl-2; 4-aminopyrazol [3,4-d] pyrimidin-2-yl; 6-purinyl; 6,8-dihydroxy-2-purinyl; benzothiazol-2-yl; benzoxazol-2-yl; benzimidazol-2-yl and derivatives thereof substituted in the benzene ring with alkoxy and halo substituents; quinolin-2-yl; 7-trifluoromethyl-quinolin-4-yl.
The aryl and the heterocyclic radical of R.sub.4 may be linked to the sulfur atom by means of an alkyl chain, this alkyl chain being preferably a C.sub.1 -C.sub.4 alkyl chain.
When R.sub.4 is a mono-or a poly- substituted C.sub.2 -C.sub.12 alkyl chain, optionally interrupted by one or more oxygen or sulphur atoms, this chain is preferably the residue of C.sub.2 -C.sub.12 alkyl thiols such as: 3-phenyl-propane-1-thiol, 3-cyclohexyl-propane-1-thiol, 3-cyclopentyl-propane-1-thiol, 2-propene-1-thiol, 2-propyn-1-thiol, 2-mercapto-1-ethanol, and ether or thioethers thereof such as 2-methoxy-ethane-1-thiol, 2-ethoxy-ethane-1-thiol, 2-propoxyethane-1-thiol, 2-isopropoxy-ethane-1-thiol, 2-pentoxyethane-1-thiol, 2-phenoxyethane-1-thiol, 3-phenoxy-propane-1-thiol, 2-methylthio-ethane-1-thiol, 2-ethylthio-ethane-1-thiol, etc.; 3-mercapto-1,2-propanediol and 1,2-acetals thereof; 2-furyl-methanethiol, 2-(2-furyl)ethane-1-thiol, 2-(2-thienyl)ethane-thiol, 2-(3-thienyl)ethane-1thiol, 2-(4-methyl-5-thiazol)ethane-1-thiol, 2-(imidazol-1-yl)ethane-1-thiol, 2-(.beta.-pyridyl)ethane-1-thiol, 3-(imidazol-1-yl)propane-1-thiol, 2-(.gamma.-pyridyl)ethane-1-thiol, 2-(pyrrol-1 -yl)ethane-1-thiol, 2-(2,5-dimethyl-pyrrol-1-yl)ethane-1-thiol, 3-(2,5-dimethyl-pyrrol-1-yl)propane-1-thiol; alkylamino-alkylthiols such as 2-dimethylaminoethane-1-thiol, 2-diethylamino-ethane-1-thiol, 2-butylamino-ethane-1-thiol, 2-(N-morpholine)ethane-1-thiol, 2-(N-pyrrolidinyl)ethane-1-thiol, 2-(N-piperidinyl)ethane-1-thiol, 2-(4'-N-substituted-piperazin-1-yl)ethane-1-thiol; aminoalkylthiols such as cysteamine, homocysteamine, 4-aminobutane-1-thiol and derivatives thereof wherein the aminogroup is protected as BOC, acylamide or cyclic imide; 3-amino-, 3-monoalkylamino and 3-dialkylaminopropane-1-thiols; mercaptoacids i.e. thioglycolic, thiolactic and thiomalic acid and derivatives thereof such as esters, amides and nitriles; .alpha.-amino acids containing thiol groups such as cystein, homocystein and polypeptides obtained starting from these aminoacids as well as glutathion; R.sub.5 is preferably methyl, ethyl or isopropyl; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are preferably hydrogen.
When one of P.sub.1 and P.sub.2 is an acyl group, it is preferably a C.sub.1 -C.sub.4 acyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), optionally substituted benzoyl with nitro or methoxy groups.
When NP.sub.1 P.sub.2 is a cyclic imide, it is preferably a cyclic imide obtained starting from succinic, glutaric, maleic, 2,3-diphenylmaleic, phtalic, hexahydro or tetrahydrophtalic acids.
When A is a masked carbonyl function it is preferably 1,3-dioxolane and a dimethoxy or diethoxyacetal.
The non toxic salts that are pharmaceutically acceptable include the hydrochlorides, hydrobromides, hydroiodides, (lower)alkylsulfates, (lower)alkyl and aryl sulfonates, phosphates, sulfates, maleates, fumarates, succinates, tartrates, citrates, and others commonly used in the art.
The salts obtained through the variation of the acid used in some cases have special advantage due to increased stability, increased solubility, decreased solubility, ease of crystallization, lack of objectionable taste, etc., but these are all subsidiary to the main physiological action of the free base, which is independent of the character of the acid used in the preparation of the salt.
Specific examples of preferred compounds of the invention are
The compounds of the inventions are prepared by a process comprising: a) reacting a compound of formula II ##STR6## wherein R.sub.1, R.sub.2, R.sub.3 are as defined above and Hal is chlorine, bromine, iodine, with a thiol of formula III
b) reacting a compound of formula Ia ##STR7## wherein R.sub.1, R.sub.2, R.sub.3 are as defined above and .phi.' is a member selected from the group consisting of a thiol and of a masked thiol group such as thio-C.sub.2 -C.sub.12 alkanoylester or a thiouronium salt --S--(C.dbd.NR.sub.8)NR.sub.9 R.sub.10 /.sup.(+) Y.sup.- with a compound of formula IV
c) reacting a compound of general formula V
d) cyclizing a compound of formula VI ##STR9## wherein R.sub.1 is as above defined, with an alkylidene compound of formula VII ##STR10## wherein R.sub.2, R.sub.4 and n are as defined above and R'.sub.5 is a substituted or an unsubstituted C.sub.1 -C.sub.6 alkyl chain, a C.sub.3 -C.sub.6 alkenyl chain, an unsubstituted or substitued aryl or C.sub.1 -C.sub.4 aralkyl, to give a compound of formula Ic ##STR11## wherein R.sub.1, R.sub.2, R'.sub.5, R.sub.4 and n are as defined above and, if desired, after removal of the known protecting group possibly present in R.sub.4, converting a compound of formula I in another compound of formula I and/or, if desired, salifying a compound of formula I and/or, if desired, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers;
e) reducing a compound of formula Id ##STR12## wherein R.sub.1, R.sub.2, R.sub.3, m are as above defined and P' is hydrogen or C.sub.1 -C.sub.8 alkyl, (CH.sub.2).sub.p.sub.1, --W, with a borohydride and/or a cyanoborohydride of an alkaline metal or of a quaternary ammonium salt, in the presence of an ammonium salt of formula VIII
f) reducing an ammonium salt of formula Ig ##STR15## wherein R.sub.1, R.sub.2, R.sub.3, m, P'.sub.2 are as above defined and r is an integer from 3 to 4 and Y.sup.- is a monovalent anion, by reaction with an alkaline or quaternary ammonium salt of a borohydride and/or a cyanoborohydride to give a compound of formula Ih ##STR16## wherein R.sub.1, R.sub.2, R.sub.3, m, r and P'.sub.2 are as above defined, which, if desired, may be optionally subjected to separation of the diastereoisomers;
g) cleavaging an oxirane ring of a compound of formula (Ii) ##STR17## wherein R.sub.1, R.sub.2, R.sub.3, B, n, n.sub.1 and p are as defined above, with a nucleophilic compound selected from the group consisting of water, C.sub.1 -C.sub.3 lower alcohols, C.sub.1 -C.sub.3 lower alkylthiols, ammonia, a monoalkyl or a dialkylamine, to give a compound of formula (Il) ##STR18## wherein R.sub.1, R.sub.2, R.sub.3, B, n, n.sub.1 and p are as above defined and one of R.sub.11 and R.sub.12 is hydroxy and the other may be hydroxy, --NH.sub.2, C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 alkylthio, a monoalkyl or a dialkylamine.
Both the process of the invention comprising the reaction of a compound of formula II with a thiol of formula III to produce a compound of formula I and the process converting a thiol or a masked thiol of formula Ia in another compound of formula I, wherein .phi. is-SR.sub.4, by treatment with a reagent of formula IV, represent an usual method pursued in the art for introducing thiols and thioether groups in an organic substrate.
The process may be respectively performed by reaction with either stoichiometric amounts or a small excess of the reagents of formula III and of formula IV in a solvent, miscible or immiscible with water, in homogeneous or in heterogeneous phase or in phase-transfer conditions, in the presence of a base in equimolar amounts or in excess.
Suitable solvents are C.sub.1 -C.sub.5 alcohols; amides such as formamide, dimethylformamide, dimethylacetamide; cyclic or linears ethers such as dimethoxyethane, dioxane, tetrahydrofuran, dimethylsulphoxide, ketones and acetales such as acetone, butanone, methylale; esters such as ethylacetate, ethylformiate; halogenated hydrocarbons such as CCl.sub.4, CH.sub.2 Cl.sub.2, 1,2-dichloroethane; aliphatic hydrocarbons such as n-hexane, n-heptane; cycloaliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, pyridine, as well as mixtures thereof.
The reaction may be carried out at temperatures ranging from about -30.degree. C. to about 100.degree. C.; preferably from about -15.degree. C. to about 60.degree. C. and more preferably from 0.degree. C. to room temperature.
The reaction times range from few minutes to two days, but usually do not exceed two hours when it is carried out at room temperature.
Preferred bases may be an inorganic base, e.g., an alkaline or an alkaline-earth hydroxide, carbonate, bicarbonate, hydride, amide e.g. NaOH, K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, Li.sub.2 CO.sub.3, KHCO.sub.3, MeONa, EtONa, ter-buOK, (EtO).sub.2 Mg, CaH.sub.2, NaH, NaNH.sub.2 ; or an organic base such as alkylamine e.g. isopropylamine, cyclohexylamine, butylamine, triethylamine, or an aromatic base e.g. pyridine or an alkylsubstituted pyridine or cyclic amines e.g. N-methyl-piperidine and 1,4-diazabicyclo[2,2,2]octane.
The reaction of a compound of formula VII with a compound of formula V is carried out with an excess of the compound of formula V e.g. at least 1.1 molar equivalents per mole of the compound of formula III preferably in presence of tetramethylguanidine as a catalyst, in inert solvents e.g. esters, halogenated hydrocarbons, linear or cyclic ethers or aromatic hydrocarbons, C.sub.1 -C.sub.5 alcohols preferably at room temperature.
The thioether bond of a compound I may be selectively oxidized to give a sulphoxide or a sulphone, according to known methods. Selective oxidation of a sulphide to sulphoxide may be performed using one molar equivalent of an organic peracid such as perbenzoic, m-Cl-perbenzoic, monoperphtalic, peracetic, performic and peroxytrifluoroacetic acid or using periodic acid or a salt thereof. Two molar equivalents or an excess of a peracid mentioned above are used for obtaining the corresponding sulphones starting from a sulphide of formula I (n=0), and one molar equivalent is necessary for the conversion of a compound of formula I (n=0) into a compound of formula I (n=2).
Suitable solvents are those which are inert to the oxidizing reagent; the reaction may be performed in the presence of an insoluble inorganic base such as Na.sub.2 CO.sub.3, KHCO.sub.3, NaHCO.sub.3 in order to remove the reduced acid from the reaction mixture; preferably the reaction is carried out at temperatures ranging from 0.degree. C. to room temperature and the reaction times range from few minutes to a few hours. The 1,4-dihydropyridine ring is not oxidized to pyridine ring under said reaction conditions.
The cyclization of a compound of formula VI with a compound of formula VII to give a compound of formula Ic may be carried out by reaction with either stoichiometric amount or a small excess of the enamine VI in inert solvents such as benzene, toluene, tetrahydrofuran, CH.sub.2 Cl.sub.2, CHCl.sub.3, 1,2-dichloroethane, pyridine, acetic acid, C.sub.1 -C.sub.5 lower alcohols; or mixture thereof.
The reaction is preferably carried out at temperatures ranging from room temperature to the reflux temperature of the reaction mixture; the reaction is preferably carried out in a temperature range from 45.degree. to 80.degree. C.; as a consequence, the reaction times may vary from several days to few hours, but usually do not exceed four hours.
A reduction of the reaction time may be achieved by addition of catalytic amount of an inorganic or organic acid e.g. hydrochloric, p-toluensulphonic or acetic acid, to the cooled reaction mixture after 2-3 hours heating.
Preferred compounds of the invention are compounds of formula (I) having a mono- or polysubstituted thioether group. Particularly preferred substituents are hydroxy, amino, carbonyl, carboxyl, epoxy groups, which may be optionally protected with protective groups removable selectively and under mild reaction conditions.
Known protective groups are, for example, acetalethers, emolethers, silylethers for alcoholic and phenolic groups, amide and 3,5-dimethylpyrrol for primary amines, acetals and ketals for carbonyl compounds, ter-butyl and alkoxymethylester for carboxylic acids; all said protective groups may be removed easily by acid hydrolysis.
Cyclic imides may be used to protect primary amino groups and their removal may be easily carried out by treatment with hydrazines or other amines e.g. butylamine.
Analogously,isothiouronium salts and alkanoylthioesters may also be used to protect thiol groups; their removal is easily carried out by treatment with ammonia or lower alkyl amines. It should be understood that functional groups such as amino, hydroxy, carbonyl, thiol, carboxyl optionally present in R.sub.4, R'.sub.4, R".sub.4 groups in the compounds of formula III, IV, V and VII, may be present either in free or protected form: in the latter case, they may be deprotected in any convenient step of the synthetic process.
On the other hand, free amino, hydroxy, thiol,carboxylic groups optionally present in the compounds of formula I, may be optionally converted into amides, Schiff bases, esters, silyl derivatives to make the purification process of the final compounds easier.
On the other hand, using methods well-known in the art, reduction (for example with alkaline borohydride or cyanoborohydride or with their tetraalkylammonium salts) of Schiff basesyields secondary amino groups, while reduction of esters of .alpha.-aminoacid yields .alpha.-aminoalcohols, intermediates for 5-dihydrooxazol-2-ones. Similarly, vicinaldiols, if present in R.sub.4, may be converted into epoxides, via monoalkyl(aryl)sulphonates, the epoxide may be cleaved to produce for example .alpha.-hydroxy-alkylamines, .alpha.-hydroxyalkylthiols, .alpha.-hydroxyether (or thioethers).
Finally, reductive amination may be used to convert a carbonyl compound of formula Id into an amino compound of formula Ie. Particularly preferred reductive amination is that of a salt of a bifunctional .gamma.- (or .delta.)-aminoketone of formula Ig into cyclic amine of formula Ih.
The starting materials of formula III, IV, V, VI are known compounds, commercially available and/or easily preparable with known methods.
The 2-halomethyl-1,4-dihydropyridines of formula II are described in the italian Pat. Appln. No. 21875 A/85 (6.8.1985) in the applicant's name.
The compounds of formula VII are prepared by reaction of an aldehyde of formula VIII
When the .beta.-ketoesters of formula IX are unknown compounds, they may be prepared using known methods starting from the known acids of formula X ##STR20##
An activated form of acid of formula X (e.g. chloride, imidazolide) may be reacted with Meldrum acid or with the magnesium enolate of a malonic acid emiester. For more detailed illustrations of general methods for .beta.-ketoester synthesis see for ex. Y. Oikawa et al., J. Org. Chem. 43, 2087 (1978), D.G. Melillo et al., Tetrah. Lett. 21, 2783 (1980) and D.C. Brooks et al., Angew. Chem. Int. Ed., 18, 72 (1979).
The compounds of the invention of formula I protect cellular membranes form oxidative injuries; a reduced malondialdehyde formation is observed after incubation of rat erithrocyte membranes (M. Aishita et al., Arch. Intern. Pharmacodyn. 261, 316, 1983) and of rat brain homogeneate (Stocks et al., Clin. Sci. Molec. Med., 47, 215, 1974) with the compounds of the invention.
Sudden death induced by bolus of arachidonic acid or of a mixture of ADP and collagene in mice and rabbits is prevented by previous oral and/or intraperitoneal treatment with the compounds of formula I.
The compounds of the invention were tested, according to the Godfraind's procedure (T. Godfraind et al., Arch. Intern. Pharmacol., 172, 235, 1968), to evaluate their property of inhibiting the contraction induced by CaCl.sub.2 in K.sup.+ -depolarized aorta strips, in comparison to nifedipine.
Many compounds of the invention showed ID.sub.50 ranging from 10.sup.-7 to 10.sup.-10 (nifedipine, ID.sub.50 2.7.10.sup.-8).
The antihypertensive activity of the compounds of the invention was also tested, at different times, after oral administration to conscious spontaneously hypertensive rats (SH rats), measuring the decrease of the mean blood pressure (B.P.).
Some compounds of the invention induce a 15% decrease at least, of the basal values of the mean B.P. when administered at a dose level lower than 1/10 of the corresponding LD.sub.50.
A 15% decrease of the mean B.P. is generally considered to be a predictive indication for a significant cardiovascular activity.
It is to be pointed out that a satisfactory correlation is not often observed between the calcium antagonist potency, as measured by "in vitro" test, and the antihypertensive activity shown "in vivo" by some compounds of the present inventions.
Representative examples are reported in the following table:
The activity of the compounds of the invention on the gastrointestinal tract was also studied in order to assess a) cytoprotective action against lesions induced by NSAI drugs; b) ability to prevent the ulcers induced by the method of Togagi-Okabe (Japan J. Pharmacol. 18, 9, 1968).
2-(3,2-Dihydropropyl)thiomethyl-6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridine is a representative compound of the invention having an ED.sub.50 lower than 1 mg/kg by oral administration.
The compounds of the invention are moreover useful for the control of electrolyte fluxes through membranes of blood cellular components such as platelets, leucocytes, eritrocytes and for the regulation of their deformability and reactivity against excitatory stimuli. At the cellular level, they are also useful in the control of enzymatic processes involving both activation and inhibition of calcium-dependent enzymes.
The compounds of the invention are consequently considered useful as vasodilators and hypotensive agents for the treatment of thromboembolic diseases, for treatment of myocardial, renal and cerebral ischemias. The compounds I are also particularly useful as cytoprotective and antiulcer agents at gastric level.
Dose order of 0.01 to 10 mg/kg/die and preferably ranging from 0.05 and 5 mg/kg/die can be given 1 to 2-3 times a day, the exact dose depending on the age, weight and condition of the patient and on the administration route. A dose for oral administration may comprise, for example, from 0.05 to 70 mg of active principle.
The amount for parenteral route may vary from 0.001 to 5 mg/kg/die, preferably from 0.01 to 2 mg/kg/die.
Some monosubstituted aminoalkylthiomethyl compounds of the invention, such as 2-aminoethylthio-4-(m-nitrophenyl)-3,5-diethoxycarbonyl-6-methyl-1,4-dihydropyridine show peculiar properties such as a pronounced and long lasting antihypertensive activity at very low doses (for example 0.4 mg/kg/os) when tested in conscious SH rats and in conscious DOCA-rats (i.e. rats made hypertensive by treatment with desoxycorticosterone acetate) by oral route.
Other typical monofunctionalized compounds of the invention are for example: 2-[(2-aminoethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-m-nitrophenyl-6-methyl-1,4-dihydropyridine and the corresponding: 4-o-chlorophenyl, 4-m-trifluoromethyl-phenyl, 4-m-chloro-phenyl derivatives; 2-[(2-aminoethyl)thio]methyl-3-carboethoxy-5-carboisopropoxy-4-m-nitrophenyl-6-methyl-1,4-dihydropiridine hydrochloride; 2-[(2-N-butylaminoethyl)thio]methyl-3,5-dicarboethoxy-4-m-nitrophenyl-6-methyl-1,4-dihydropyridine and the corresponding N-methyl and N-isopropyl derivatives; 2[(2-aminopropyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-m-nitrophenyl-6-methyl-1,4-dihydropyridine and the 2-[(4-aminobutyl)thio]methyl derivatives, and salts thereof.
The antihypertensive effect is strictly dose dependent in the investigated dosage range from 1.5 to 0.1 mg/kg/os. The maximum hypotensive effect, proportional to the administered dose, takes place 6-7 hours after the administration and the blood pressure is maintained at the decreased level for other 4-5 hours, at least.
The gradual onset of the antihypertensive effect is not coupled with reflex tachycardia, which is often observed after treatment with other antihypertensive agents such as, for example, hydralazine and many dihydropyridines, in the same experimental models.
On the contrary, no substantial modifications of the mean B.P. and heart rate are observed in normal conscious rat after oral administration of these monofunctionalized aminoalkylthiomethyl-1,4-dihydropyridines at the same dose range level (1.5-0.1 mg/kg). It should be pointed out that the same compounds, investigated "in vitro", show modest to middle inhibitory properties against CaCl.sub.2 -induced contraction of K.sup.+ -depolarized rat aorta strips with calculated ID.sub.50 ranging from 10.sup.-6 to 10.sup.-7 M. Only after prolongation of the contact time of solutions of these compounds with the tissue preparations from the standard 2-5 minutes to 2-3 hours before the CaCl.sub.2 stimulated contractions, it is possible to calculate ID.sub.50 ranging from 10.sup.-8 to 10.sup.-10 M.
The peculiar antihypertensive effect, its gradual onset, the long lasting activity lead to suppose that the compounds of formula I and more precisely those of formula Ih, Ie wherein R.sub.1 is a carboxyester group, are more specifically useful in human and veterinary therapy for treatment of hypertensive diseases of different cause and severity.
For the achievement of the desired effects in human and veterinary therapy, these compounds of formula Ie, Ih, of the invention, may be administered by oral route or by parenteral route in a variety of dosage forms e.g. orally in the form of tablets capsules or liquids; rectally in the form of suppositories, subcutaneously, intramuscularly, or intravenously administration or by infusion in emergency situation.
The amounts of active ingredient may range from 1 .mu.g to 1 mg/kg/die preferably from 1 .mu.g to 0.1 mg/kg/die by oral administration. The parenteral dosage may range from 0.1 .mu. to 0.5 mg/kg/die and preferably from 0.5 .mu.g to 0.2 mg/kg/die. One dose for oral administration may contain, for example, from 50 .mu.g to 5 mg of active ingredient.
The compounds of the invention may be administered once a day, even if administrations more or less frequent may be sometimes convenient according to the age, weight and patient's condition and to the administration route.
Suitable pharmaceutical formulation may be prepared according to conventional techniques such as those described in Remington's Pharmaceutical Sciences Handbook", Hack Publishing Co., U.S.A.
For the oral administration, the compound may be formulated in solid or liquid preparations such as capsules, pills, tablets, powders, solutions, suspensions or emulsions. The unit dosage form may be the hard or soft gelatine capsule containing for instance lubricants and inert excipients such as lactose, saccharose or starch. Alternatively, the compounds of the invention may be administered as tablets, on carriers such as lactose, saccharose or starch in combination with binders such as starch itself or gelatin, disintegrating agents such as potato starch, or alginic acid, and lubricants such as stearic acid and magnesium stearate.
For parenteral administration the compounds of the invention may be administered in injectable forms, dissolved or suspended in pharmaceutically acceptable diluents, with a pharmaceutical carrier such as a sterile liquid such as water or an oil, with or without the addition of other pharmaceutically acceptable excipients. Oils which may be used in said preparations are of mineral, vegetal, animal or synthetic kind. Generally, as a carrier for injectable solutions the following substances may be used: water, salts, aqueous solutions, dextrose or other sugars aqueous solutions, ethanol, glycols such as propylenglycol and polyethylenglycols.
For the rectal administration, the compounds may be formulated in forms of suppositories, mixed with conventional vehicles such as, for example, cocoa butter, wax, polyvinylpyrrolidone or polyoxyethyleneglycols, or derivatives thereof.
The administration route generally preferred is the oral route, while the preferred pharmaceutical formulations are capsules.
The invention is illustrated by the following non limitative examples, wherein the abbreviations "DME", "Et.sub.2 O", "AcOEt", "EtOH", "TEA", "AcOH", "THF", "MeOH" refer to 1,2-dimethoxyethane, diethylether, ethylacetate, ethanol, triethylamine, tetrahydrofurane and methanol, respectively.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 4892881 |
Alker et al. |
Jan 1990 |
|
| 4971984 |
Frigerio et al. |
Nov 1990 |
|
Divisions (1)
|
Number |
Date |
Country |
| Parent |
889379 |
Jul 1986 |
|
Patent Grant
5021436
