NZ228622A - Substituted 1,6-naphthyridine derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £28622 22 8 6 2 2 p- Dj;s j Conip.cte Soecif:cat:on Ft! { C'--c- \.X ~ '''' cd: Ia/^- & ^ JAN i39Q Under the previsions of Regulation 23 (?) iho .C.O.K)f!teX Specification ri3 been antc-catca 6 ..

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NEW ZEALAND Initial Patents Act 1953 COMPLETE SPECIFICATION '1,6-NAPHTHYRIDINE DERIVATIVES' Divided out of N.Z. No 213218 dated 23 August 1985 r -\ ,Z-5APR1989 ^1 We, GODECKE AKTIENGESELLSCHAFT, a company organised under the laws of the Federal Republic of Germany, of Salzufer 16, 1000 Berlin 10, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us , and the method by which it is to be performed, to be particularly described in and by the following statement : - 22 8 6 2 2 The present invention is concerned with new 1,6-naphthyridine derivatives, with the preparation thereof and with pharmaceutical compositions containing them.

The new 1, 6—naphthyridine derivatives according 5 to the present invention are compounds of the general formula wherein is an unsubstituted or substituted aromatic 2 or heteroaromatic ring, R is a straight-chained or 10 branched alkyl radical containing up to 4 carbon atoms 3 or a benzyl radical, R is a hydrogen atom, a straight-chained or branched alkyl radical or an alkoxycarbonyl 4 radical containing up to 4 carbon atoms, R is a straight-chained or branched alkyl radical containing up to 4 carbon atoms and R is a carboxyl group or a straight-chained, branched or cyclic alkoxycarbonyl radical which contains up to 17 carbon atoms and optionally also contains an oxygen, sulphur or nitrogen atom; as well as the pharmacologically acceptable salts 20 thereof.

As aromatic or heteroaromatic rings R^", there are preferred phenyl, thienyl, pyridyl or 2,1,3-benzoxa-di azolyl radicals which are unsubstituted or substituted once or twice by lower polar or non-polar ^radicals.

As used throughout the description and claims, the term 'a lower radical' is intended to have the meaning that would ordinarily be understood by a person working in the field of the invention, i.e. a radical having up to 6 carbon atoms. 22 8 6 22 1,6-Naphthyridine derivatives of general formula (I) are preferred in which is a phenyl radical mono— or disubstituted by halogen, cyano, nitro, lower alkyl, lower alkoxy, difluoromethoxy, trifluoromethoxy, lower alkylenedioxy, such as methylenedioxy, lower alkylamino, especially dimethyl-or diethyl amino, methylthio or trifluoromethyl radicals, or is a thienyl, pyridyl or 3 2,1,3-benzoxadiazolyl radical, R is preferably a hydrogen atom, an alkyl radical containing up to 4 carbon atoms or an alkoxycarbonyl radical containing 4 up to 5 carbon atoms, R is preferably an alkyl radical containing up to 3 carbon atoms and especially a methyl or ethyl radical and R^ is preferably a carboxyl group or an alkoxycarbonyl radical containing up to 17 carbon atoms. Complex or voluminous radicals can here be present which possibly contain further heteroatoms, such as oxygen, sulphur or nitrogen atoms. Typical examples of such radicals include amines, such as lower N-benzyl—N-alkylaminoalkyl radicals, N,N-dialkylamino-alky 1 radicals or lower alkylthioalkyl or alkoxyalkyl radicals.

Especially preferred are 1,6—naphthyridine derivatives of general formula (I) in which R1 is a phenyl radical optionally substituted preferably in the 2- or 3-position by halogen, cyano, nitro, methyl, methoxy, difluoromethoxy or trifluoromethyl or is a phenyl radical preferably substituted in the 2,3- or 22 8 6 2 2 -4~ 2,6-position by halogen atoms, v.-hich can be the same or different, or is an unsubstituted thienyl radical, 2 R is a methyl, ethyl, n-propyl, isopropyl, n-butyl, 3 sec.-butyl, isobutyl or benzyl radical, R is a hydrogen atom, preferably a methyl but also an ethyl or isopropyl radical or an alkoxycarbonyl radical of the general formula: -CO2R6 (II) in which R^ is a methyl, ethyl, propyl or isopropyl 4 radical and especially an ethyl radical, R is a methyl or ethyl radical and R~* is a carboxy group or an alkoxycarbonyl radical of the general formula: -CO2R7 (III) 7 in which R is a hydrogen atom, a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or benzyl radical, an alkoxy alkyl or alkyl thioalkyl radical of the general formula: - ( CH2) n—0-R8 or - (CH2 ) n—S—R8 (IV) (V) g in \Aiich R is an alkyl radical containing up to 3 carbon atoms and n is 2 or 3, or an ami no alkyl radical of the general formula: ^ R9 — (CH2)n-S^ 1Q (VI) R 22 8 6 2 2 9 10 in which R and R can be the same or different and are hydrogen atoms, straight-chained or branched alkyl radicals containing up to 4 carbon atoms or benzyl radicals or together form a lower alkylene radical and n is 2 or 3.

The present invention also provides a process for the preparation of 1,6-naphthyridine derivatives of general formula (I), wherein 1,6-naphthyridinone derivatives of the general formula: 13 4 in which R , R and R have the same meanings as above • and R is an alkoxycarbonyl radical of general formula (III), are alkylated in known manner.

Compounds of general formula (I), in which R^ is a carboxyl group, are preferably prepared from compounds of general formula (I), in which R is a benzyloxy-carbonyl radical, by hydrogenolytic fission in known manner.

The congpounds of general formula (VII) can be prepared, for example, in the manner described in European Patent Application No 133530 in that either a) a dihydropyridine of the general formula:- V* /> 2 8 6 2 (VIII) 1 3 4 5' in Which R , R , R and R have the same meanings as above, is reacted with s-triazine in the presence of a base, b) a 1,4—dihydropyridine of general formula (VIII) is reacted vdth a dialkylformamide diallcyl acetal of the general formula _12 11 N / - CH (IX) 12 \^011 R OR 12 in vdaich the R substituents can be the same or 10 different and are methyl or ethyl radicals and each of the substituents is an alkyl radical containing up to 4 carbon atoms or the two R^ substituents together represent an alkylene radical containing up to 3 carbon atoms, and the compound obtained of the general formula: > 12 (X) in which R1, R3, R4, R5' and R12 have the same meanings as above, is reacted with ammonia, or 22 8 6 22 c) 2,4-dihydroxypyridine is reacted with a compound of the general formula: *5' RX - CH = C ^ . (XI), ^ COR 1 5' in which R and R have the same meanings as above 4* and R is a straight-chained or branched alkyl radical containing up to 4 carbon atoms, in the presence of ammonia.

The compounds of general formula (XI) are known or can be prepared by processes known from the literature (see Org. Reactions, 1,5, 204 et seq./1967). 2,4-Dihydroxypyridine is commercially available.

The 1,4-dihydropyridines of general formula (VIII) used for processes a) and b) are known (cf., for example, Chent. Rev., 82, 223/1982) or can be prepared in an analogous manner.

For carrying out process a), the 1,4-dihydro-pyridine derivative is heated with s-triazine in an inert organic solvent in the presence of a strong base, for example an alkali metal alcoholate or sodium hydride, to a temperature of from 50 to 160°C. and preferably of from 100 to 150°C. As solvents, there are here especially preferred polar solvents, such as dimethyl sulphoxide, dimethylformamide, ethylene glycol dimethyl ether or lower alcohols, such as ethanol- For carrying out the reaction according to process variant b), the appropriate 1,4-dihydropyridine 22 8 6 2 2 derivative is reacted vdth an equivalent or excess amount of dialkyl formamide clialkyl acetal, preferably in the presence of an aprotic solvent, such as dime thy If ormamide, dimethyl sulphoxide or hexamethyl-phosphoric acid triamide, while heating. Especially preferred formamide acetals include dimethylformamide dimethyl acetal and dimethylformamide diethyl acetal.

The intermediate of general formula (X) obtained according to process variant b) is converted into a compound of general formula (VII) by reaction with ammonia in the presence of a preferably protic solvent at ambient temperature or at an elevated temperature, preferably at the boiling point of the solvent used. As solvents, there are especially preferred lower alcohols, such as methanol or ethanol.

Reaction c) is preferably carried out in inert organic solvents, especially lower alcohols, such as methanol, ethanol or isopropanol. It is also expedient to work at elevated temperatures, preferably at the boiling temperature of the solvent used. The reaction products can be isolated and purified by known separation processes, such as crystallisation and/or chromatography.

The preparation of the 1, 6-naphthyridine derivatives of general formula (I) takes place, according to the present invention, according to conventional processes described in the literature for the 0— 22 8 6 2 2 alkylation of lactams (cf. Adv. Heterocyclic Chem. , 12, 185-212/1970). Appropriate alkylation agents include alkyl halides and alkyl sulphonates, dialkyl sulphates and trialkyloxonium salts.

For the reaction with alkyl halides, the compounds of general formula (VII) are used in the form of their metal salts, preferably of their alkali metal or silver salts, which are either prepared separately or are produced in situ with the help of appropriate bases, such as metal hydrides, carbonates or alkoxides in aprotic solvents.

As appropriate solvents, depending upon the alkylation agent used, there can be used practically all inert organic solvents, such as open-chained, cyclic or also aromatic hydrocarbons, for example n-pentane, n-hexane, cyclohexane, benzene or toluene, halogenated hydrocarbons, such as dichloromethane or 1,2-dichloroethane, ethers, such as diethyl ether or 1,2-dimethoxyethane, as well as dipolar aprotic solvents, such as dimethylformamide, hexamethyl-phosphoric acid triamide and dimethyl sulphoxide. Depending upon the solvent used, the temperature range can be varied between -20°C. and the boiling point of the solvent in question.

Because of the ambident character of the lactam anion, in the case of the alkylation there are frequently obtained mixtures of 0- and N-alkylation (m 22 8 6 2 2 products, depending upon the reaction conditions and the alkylation agent used (see J. Org. Chem., 32. 4040 et seo./1967). The product mixtures obtained may be separated by chromatographic methods and/or by crystallisation.

The 1,6-naphthyridine derivatives of general 2 formula (I) in which R is a methyl or ethyl radical are preferably obtained by reaction of the 1,6-naphthyridinones of general formula (VTI) with trimethyl 10 or triethyloxonium salts, especially trimethyloxonium tetrafluoroborate, in an aprotic solvent. The preparation of the 0-propyl, 0-isopropyl, 0-butyl, O-sec.-butyl, 0-isobutyl and 0-benzyl compounds, on the other hand, is preferably carried out by alkylation of the 15 alkali metal salts with appropriate alley 1- or benzyl halides, Acidic or basic compounds of general formula (I), in which R is a carboxyl group or an unsubstituted or substituted aminoalkoxycarbonyl radical, are, for the purpose of purification and from galenical reasons, 20 preferably converted into crystalline, pharmacologically acceptable salts.

When R is a carboxyl group, with the use of bases, for example hydroxides or carbonates, there can be prepared the corresponding salts of the alkali metals 4 or alkaline earth metals. When the substituents R and/or R have a basic character, salts are obtciined in conventional manner by neutralisation of the bases 22 8 6 2 2 with appropriate inorganic or organic acids. As acids, there can be used, for example, hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicylic acid, ascorbic acid, malonic acid, or succinic acid.

Since the compounds of general formula (I) according to the present invention have a chiral centre on C4, they can be present either as racemic mixtures or in the form of the enantiomers.

The compounds of general formula (I) are highly effective calcium antagonists. In contradistinction to known calcium antagonists, at therapeutic concentrations a cardiodepression (negative inotropic, negative chronotropic action) is not to be expected.

On the basis of their blood vessel spasmolytic actions, they are especially indicated in the case of cerebral, cardial and peripheral blood vessel diseases, such as myocardial ischaemia, cerebral infarct, pulmonary thromboses and arteriosclerosis and other stenotic indications, especially because, in comparison with known compounds with a similar mode of action, negative inotropic side effects are substantially absent. Therefore, the 1,6-naphthyridine derivatives of the present invention are valuable agents for combating heart-circulation mortality. 228522 Consequently, a further subject of the present invention is the use of 1,6-naphthyridine derivatives of general formula (I) for combating blood vessel diseases.

The compounds of general formula (I) according to the present invention can be administered orally or parenterally in liquid or solid form. As injection solution, water is preferably used which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents or buffers.

Additives of this kind include, for exanple, tartrate and citrate buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the nontoxic salts thereof), as well as high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration cam, if desired, also contain flavouring and/or sweetening agents.

Individual dosages to be administered enterally are in the range of from about 5 to 250 mg and prefer- 22 8 6 2 2 ably from 20 to 100 mg. Parenterally, about 1 to 20 mg. are administered.

The following Examples are given for the purpose of illustrating the present invention:-Example 1.

Methyl (-)— 4—(2—fluorophenyl)-l,4— dihvdro-5-isooropoxv-2—methyl-1.6-naphthvridine-3-carboxvlate. 1.1 g. (37 mMol) sodium hydride (80% in paraffin oil) are suspended in 70 ml. dry dimethylformamide and a solution of 10 g. (32 mMol) methyl ( + )-4—(2-fluoro-phenyl)-l,4,5,6-tetrahydro-2-methyl-5-oxo-l,6-naphthyridine-3-carboxylate in 100 ml. dimethylformamide is added dropwise thereto at eimbient temperature, while stirring. After cessation of the evolution of gas, the reaction mixture is further stirred for 30 minutes at ambient temperature. 5.9 g. (35 mMol) isopropyl iodide in 30 ml. dimethylf ormamide are then added. Stirring is continued for 20 minutes at ambient temperature, the solvent is evaporated off in a rotary evaporator and the oily residue is stirred with 100 ml. water. The resulting pale brown crystalline mass is filtered off with suction, washed with water and dried.

For purification of the crude product, it is crystallised from a mixture of 400 ml. ethyl acetate and 50 ml. methanol, the 0-alkylation product remaining in highly enriched form in the mother liquor as a readily soluble component. This is first chromatographed 22 8 6 2 2 over silica gel with dichloromethane/methanol (9:1 v/v), starting material still present thereby being completely separated. Further chromatography over silica gel with toluene/ethyl acetate (3:1 v/v) gives almost pure methyl (±)-4-(2-fluorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-l,6-naphthyridine-3-carboxylate (= 0.3). Finally, crystallisation from n-hexane/diisopropyl ether gives TLC-pure crystals; m.p. 164 - 165°C.

The methyl (±)-4-(2-fluorophenyl)-l,4,5,6-tetra-hy d ro— 2 -me thy 1 - 5 - oxo-1,6-naphthyridine- 3-carboxylate used as starting material is prepared as follows: A solution of 31.5 g. (120 mMol) dimethyl 4-(2-fluorophenyl)-l,4—dihydro—2,6-dimethylpyridine-3,5-dicarboxylate in 260 ml. dimethylf ormamide is added dropwise, tinder an atmosphere of nitrogen, to a suspension of 3.8 g. (130 mMol) sodium hydride (80% in paraffin oil) in 60 ml. dry dimethylf ormamide. Upon slowing down of the evolution of gas, the reaction mixture is further stirred for 10 minutes at ambient temperature and subsequently 10.0 g. (120 mMol) s-triazine in 260 ml. dimethylf ormamide are added drop-wise thereto. The reaction mixture is heated to 110°C. for 16 hours and, after cooling, evaporated in a vacuum. The dark residue is stirred with 600 ml. acetone, filtered and the filtrate evaporated in a vacuum. The crude product is boiled with 300 ml. methanol, the crystals formed after cooling are 22 8 6 2 filtered off and, for further purification, are re-crystallised from methanol. There is obtciined methyl (+)-4— (2-f luorophenyl )-l, 4,5,6— tetrahydro-2-methyl-5-oxo-1,6-naphthyridine—3—carboxylate in the form of 5 pale beige crystals: m.p. 315 - 316°C. (decomp.).

The following conpounds are obtained in an analogous manner: methyl (- )-4- (2-bromophenvl )-l, 4-dihvdro-5-isopropoxy-2—methyl-1, 6— naphthvridine-3-carboxylate (1. a) : m.p. 10 2 01 - 202°C., recrystallised from diisopropyl ether methyl (-)-l,4—dihvdro-5-isopropoxv-2-methyl-4-(2-nitrophenvl)-l,6-naphthyridine-3—carboxylate (l.b); m.p. 170°C., recrystallised from diisopropyl ether/ methanol methyl f — )-l, 4— dihvdro-5-isopropoxy-2-methyl—4—phenyl— 1,6-naphthyridine-3-carboxylate (l.c); m.p. 132 -133°C. , recrystallised from n-hexane methyl (-)-4—(3-chloro-2-fluorophenyl )-l,4-dihydro-5-isopropoxy-2-methyl-l.6-naphthyridine-3-carboxylate 20 (l.d); m.p. 166 - 167°C. , recrystallised from n-hexane methyl (- )-l, 4—dihvdro-5-isopropoxy-2-methvl—4- (3-nitrophenyl)-l. 6-naphthyridine-3-carboxylate (l.e): m.p. 174 - 175°C. , recrystallised from n—hexane methyl f -)—1,4—dihydro— 5-isopropoxy-2-methyl—4— (2-25 trifluoromethylphenyl )— 1, 6-naphthyridine-3-carboxylate (l.f); m.p. 199 - 200°C., recrystallised from diisopropyl ether 22 8 6 2 2 methvl f- )—4-( 2—chloro-6-fluorophenyl)-1.4-dihydro-5-isopropoxv-2-methyl-l.6-naphthyridine-3-carboxvlate (l.g); m.p. 194 - 195°C., recrystallised from diisopropyl ether methyl (-)-l.4-dihvdro-2-methyl-5-propoxv-4—(2-trifluororaethylphenyl)-l.6-naphthvridine—3-carboxvlate (l.h); m.p. 151 - 152°C., recrystallised from n-hexane/dii sopropyl ether methyl (—)-4—f2—bromophenyl)—5—ethoxv-1,4—dihvdro-2-methyl-1, 6-napht"hvridine-3-carboxvlate (l.i); m.p. 203 - 204°C., recrystallised from toluol/ethyl acetate ethvl (-)—5—butoxy-1,4-dihvdro—2-methyl-4-(2-trifluoromethylpbenvl )-l. 6-naphthyridine-3-carboxylate (l.j); m.p. 107 - 109°C., recrystallised from n-hexane 2—methoxyethyl (—)-1,4-dihydro-5-isopropoxy- 2-methyl -4—(3-nitrophenvl)-l.6-naphthyridine-3-carboxylate (l.k); m.p. 174 - 175°C., recrystallised from diisopropyl ether ethyl (-)-l.4-dihvdro—5—isopropoxy-2—methyl-4-(2— trifluoromethylphenvl)-l,6-naphthyridine-3-carboxvlate (1.1): m.p. 102 - 103°C., recrystallised from n-hexane i sopropyl (-)-1,4—dihydro-5-isopropoxy-2-methyl-4—(2— trifluoromethylphenvl)—l.6-naphthyridine-3-carboxylate (l.m); m.p. Ill - 112°C., recrystallised from n-hexane isobutyl (—)—1,4—dihydro—5—isopropoxy—2—methyl—4—(2— trifluoromethylphenvl)-l.6—naphthvridine-3-carboxvlate (l.n); m.p. 115 - 116°C., recrystallised from n-hexane 22 8 6 2 2 ethyl (-)-•4— (2,3-dichlorophenvl)-1.4- dihvdro—5-isopropoxy—2—methyl—1,6—naphthvridine-3-carboxvlate (l.o); m.p. 272 - 273°C., recrystallised from diisopropyl ether ethyl (-)-5-sec.-butoxv-1,4-dihvdro-2-methvl—4—(2-trifluoromethvlphenyl)-l,6-naphfhvridine-3-carboxylate hydrochloride (l.p): m.p. 148 - 150°C., recrystallised from diisopropyl ether/ethyl acetate ethyl (- )-l, 4-dihvdro-5-isobutoxv-2-methvl-4- ( 2-trifluoromethvlphenyl)-l,6-naohthyridine-3-carboxvlate (l.q); m.p. 118 - 119°C., recrystallised from petroleum ether (b.p. 60 - 80°C.) tert.—butyl (—)—1,4—dihvdro-5—isopropoxy—2-methyl—4— (2-trifluoromethvlphenyl)—1,6-naphthyridine-3-carboxylate (l.r): m.p. 209°C., recrystallised from n-hexane/diisopropyl ether ethyl (-)-2-ethvl-l.4—dihvdro-5-isopropoxy-8-methvl-4-phenyl-1,6-naphthvridine-3-carboxylate (l.s); m.p. 176 - 177°C., recrystallised from n-hexane/diisopropyl ether 2- (N-benzvl—N-methvlamino)-ethyl ( — )-l ,4—dihydro-5— isopropoxy-2-methyl-4- (3-nitrophenyl )-l, 6-naphthvridine- 3-carboxylate dihydrochloride (l.t)y m.p. 148 - 150°C., recrystallised from ethyl acetate/acetonitrile 2-dimethylaminoethyl (-)-l,4-dihydro-5-i sopropoxy—2-methyl-4—(3-nitrophenyl)-l,6-naphthyridine-3-carboxylate dihydrochloride (l.u); m.p. 148 - 150°C., recrystallised from diisopropyl ether 228622 2-methvlthio-ethyl (- )-l ,4— dihvdro-5-isopropoxv-2-methyl-4—(3-nitrophenyl)-l,6-naphthvridine-3-carboxylate (l.v); m.p. 154- — 155°C., recrystallised from diisopropyl ether/ethyl acetate 5 2— (N-benzyl-N-methy 1 amino)-ethyl (-)-l, 4-dihvdro-5-i sopropoxy-2-methvl-4—(2-trifluoromethvlphenvl)-l.6-naphthyridine-3—carboxylate dihydrochloride (l.w); m.p. 163 - 165°C. (decomp.), recrystallised from acetonitrile diethyl (-)-l,4—dihvdro-5-isopropoxv-2-methvl-4-(2- trifluoromethvlphenyl)-l,6—naphthvridine-3,8-dicarboxvlate (1.x); m.p. 140 - 141°C.# recrystallised from n-hexane ethyl (-)-l, 4—dihydro-5-i sopropoxy-2-me thvl-4- (2-trifluoromethylphenyl)-l. 6—naphthvridine-3-carboxylate 15 hydrochloride (l.y); m.p. 137°C., recrystallised from ethyl acetate ethyl (-) — 1,4—dihydro—5-i sop ropoxv-4— (2—methoxvphenyl )— 2-methyl-l, 6-naphthyridine-3—carboxylate (l.z); m.p. 145 - 146°C. , recrystallised from n-hexane/dii sopropyl 20 ether ethyl (-)—1.4—dihvdro—5-i sopropoxy-2-methvl-4- (2-thienyl)-l,6-naphthyridine-3—carboxylate (l.aa); m.p. 110 - 111°C., recrystallised from n-hexane ethyl (-)— 4— (2-cvanophenyl )-l, 4—dihydro— 5-i sopropoxy-2-25 methyl-1, 6-naphthyridine-3-carboxylate (l.ab)r m.p. 182 - 183°C., recrystallised from n_-hexane/diisopropyl ether 22 8 6 2 ethyl f-)-5-ben2vloxv-l,4-dihvdro-2-methvl-4—(2-trifluoromethvlphenvl )-l. 6-naphthyridine-3-carboxvlate (l.ac): m.p. 142 - 143°C., recrystallised from n-hexane/diisopropyl ether ethvl (—)—2—ethvl-1,4—dihydro—5—isodropoxv—8—methvl-4— (2-trifluoromethvlphenyl)-l,6—naphthvridine-3-carboxylate (l.ad); m.p. 112 - 113°C., recrystallised from n-hexane benzyl (-)-l, 4— dihvdro-5—isopropoxy-2-methv1-4-(2-trifluoromethvlphenyl)-l.6-naphthvridine-3-carboxylate (l.ae): m.p. 126 - 127°C., recrystallised from n-hexane 2-dimethvlaniinoethvl (-)-l,4-dihydro-5-isopropoxy-2-methyl-4- (2-trif luoromethvlphenyl )-l, 6-naphthyridine- 3-carboxvlate (l.af); m.p. 104 — 105°C., recrystallised from n-hexane 3-dimethylaminopropyl (- )-l,4— dihydro— 5-isopropoxy— 2— methyl-4—(3-nitrophenyl)-l.6-naphthyridine-3-carboxylate (l.ag): m.p. 134 - 136°C., recrystallised from n-hexane/diisopropyl ether ethyl (-)—4—(2-difluoromethoxyphenyl)-l,4—dihvdro-5-isopropoxy-2-methyl-1,6-naphthvridine-3-carboxylate (l.ah); m.p.145—147°C from n-hexane/diisopropylether 2-dibenzylaminoethvl f-)-l,4—dihydro—5-isopropoxv-2- methyl-4— ( 2-trif luoromethvlphenyl )-l, 6-naphthyridine- isopropanol 3—carboxylate (l.ai) ; m.p. 132—133 C, sequiphosphate from ethyl (t)"1/4-dihydro-5-isopropoxy-2-methyl-4-(2-methyl-phenyl)-1,6-naphthyridine-3-carboxylate (1.aj); m.p. 122-124°C., recrystallised from n-hexane/diisopropyl ether 22 8 6 2 2 2-dimethvlaminoethyl (t)-l.4-dihvdro-S-isopropoxv-2-methvl—4—(3-nitrophenyl)-l,6-naphthvridine-3-carboxylate (l.aJc); m.p. 91 — 93°C., recrystallised from n-hexane/diisopropyl ether. 1.al: (- )-l. 4-Dihydro-5-isopropoxy-2-methyI-4-( 2-trifIuoromethyl-phenyl )-l. 6-naph thy ridine-3-car boxy lie acid-( 2-aminoethy 1 )-ester m.p. 166-167°C from diisopropylether/ethylacetate l.am: ( j:)-4-(2-DifIuoromethyIthiophenyI)-l .4-dihydro-5-isopropoxy-2-methyl-l. 6-naphthyridine-3-carboxylic acid ethyl ester m.p. 124-125°C from n-hexane/diisopropylether l.an: (t)-l,4-Dihydro-5-isopropoxy-2-methyI-4-(2.3-methylen-dioxy-phenyl)-!. 6-naphthyridine-3-carboxylic acid ethyl ester m.p. 156-158°C from diisopropylether/ethylacetate l.ao: (-)-l .4-Dihydro-5-isopropoxy-2-methyI-4-(2-trifluormethyI-phenyl)-!,6-naphthyridine-3-carboxylic acid-(2-piperidino-ethyl) ester m.p. 11B-120°C from n-hexane l.ap: (-)-4-(2-ChlorophenyI-l. 4-dihydro-5-isopropoxy-2-methyI-l. 6-nafrfvthyridine-3-carboxylic acid ethy] ester m.p. 135-136°C from n-hexane l.aq: (_ )-l.4-Dihydro-5-isopropoxy-2-methyl-4-phenyI-l. 6-naph-thyridine-3-carboxylic acid ethyl ester m.p. 13S-137°C from n-hexane l.ar: C*)-!,4-Dihydro-5-isopropoxy-2-methy 1-4-(2-trifluoromethy 1-phenylj-1,6-naphthyridine-3-carboxyIic acid- C3-(N-benzyl-N-methylamino)propyl 1 ester. Dihydrochlorid m.p. 143-144°C from dioxan/acetonitril l.as: (4RS)-1,4-Dihydro-5-isopropoxy-2-methy 1-4-(2-trif I uoromethyl-phenyD-l. 6-naphthyridine-3-carboxyIic acid-(R)-2-buty!ester m.p. 100°C from n-hexane 22 8 6 2 2 l.at: (4RS)-5-[(RS)-Sec-butoxy] -1.4-dihydro-2-methy]-4-(2-trifluoro-methylphenyD-l. 6-naphthyridine-3-carboxyIic acid-T2-N-benzyI-N-methylamino)ethyl] ester* Dihydrochlorid m.p.. 149-152°C from acetonitril 3.a: (t )-l, 4-Dihydro-5-methoxy-2-fnethy 1-4-(2-trif luoromethylphenyl )-1.6-naphthyridine-3-carboxyIic acid-( 2-dimethylaminoethyI )-ester m.p. 137-138°C from ethylacetate. lau.) Ethyl-(±) -4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate m.p. 134-236 *C from n-hexane lav.) N-benzyl-3-piperidinyl-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-l,6-naphthyridine-3-carboxylate m.p. 205-207 *C from diisopropylether/ethylacetate law.) N-benzyl-4-piperidinyl- (±) -l, 4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl)-1, 6-naphthyridine-3—carboxylate • sesquiphosphate m.p. 147-148 *C from isopropanol lax.) [2-(N,N-dibenzylamino) ethyl]-(±) -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1, 6-naphthyridine-3-carboxylate • sesquiphosphate m.p. 132-133 *C from isopropanol lay.) [2-(N-methyl-N-phenylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate m.p. 114-116 *C from n-hexane/diisopropylether laz.) Ethyl-(±) -4-(2-chloro-3-trifluoromethylphenyl) -l,4-dihydro-5-isopropoxy-2-methyl-l,6-naphthyridine-3-carboxylate m.p. 173-175 *C from n-hexane/diisopropylether 22 8 6 2 2 lba.) [2-(N,N-diethylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate -hydrochloride m.p. 198-200 *C from isopropanol lbb.) Ethyl - (±) -1,4 -dihydro-5-isopropoxy-2-methyl-4- (3-tr if luoromethylphenyl) -1,6-naphthyridine-3-carboxylate m.p. 130-131 *C from n-hexane lbc.) Ethyl-(±) -l, 4-dihydro-5-isopropoxy-2-methyl-4- (4-trif luoromethylphenyl) -1,6-naphthyr idine-3 -carboxylate m.p. 117-120 *C from n-hexane lbd.) Ethyl- (±) -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-pyridyl) -1,6-naphthyridine-3-carboxylate m.p. 191-193 *C from cyclohexane/ethylacetate lbe.) Ethyl-(±)-1,4-dihydro-5-ethoxy-2-methyl-4-(2- trif luoromethylphenyl) -1,6-naphthyridine-3-carboxylate m.p. 91-94 *C from n-hexane lbf.) Ethyl- (±) -1,4-dihydro-2-methyl-5-propoxy-4- (2- tr if luoromethylphenyl) -1,6-naphthyridine-3-carboxylate m.p. 115-117 *C from n-hexane lbg.) [2-(N-benzyl-N-methylamino) ethyl] - (±) -4-(2-chloro-3-trif luoromethylphenyl) -1,4-dihydro-5-isopropoxy-2-methyl-1, 6-naphthyridine-3-carboxylate • dihydrochloride m.p. > 165 "C (decomp.) from isopropanol 22 8 6 2 2 lbh.) [2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • dihydrochloride m.p. 148-150 *C from acetonitril lbi.) [2-(N-benzy1-N-methylamino)ethyl]-(±)-4-(2-cyanopheny1)-1,4-dihydro-5-isopropoxy-2-methyl-l,6-naphthyridine-3-carboxylate m.p. 120-122 *C from diisopropylether/ethylacetate Ibj.) (2-Phenoxyethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • sesquioxalate m.p. 110-113 *C from diisopropylether lbk.) [2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-methoxy-2-methyl-4-( 2-trif luoromethylphenyl) -1, 6-naphthyridine-3-carboxylate - sesquioxalate m.p. 144-146 'C (decomp.) from ethylacetate/isopropanol lbl.) Methyl- (±) -4-(2,6-dichlorophenyl) -1,4-dihydro-5-isopropoxy-2- I3ethyl-l , 6-naphthyridine-3-carboxylate ia.p. 245 *C from diisopropylether/ethylacetate lbm.) (2-Phenoxyethyl) — (±) — 1,4-dihydro-5-isobutoxy-2-methyl-4- (2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • hydrobromide m.p. 108-109 *C from ether lbn.) (2-Phenoxyethyl) -4- (2-difluoromethoxyphenyl) -1,4-dihydro-5-isopropoxy-2-methyl-l, 6-naphthyridine-3 -carboxylate m.p. 122-124 "C from diisopropylether 22 8 6 2 2 lbo.) Benzyl-(±)-l,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate m.p. 158-160 "C from ethanol lbp.) Cyclopropylmethyl-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate m.p. 112-114 *C from n-hexane lbq.) Ethyl-(±)-l/4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6- naphthyridine-3-carboxylate m.p. 180-182 *c from n-hexane/ethylacetate lbr.) (Trans-cinnamyl)-(±)-l,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • sesquioxalate m.p. 164-166 *C from ethylacetate lbs.) [2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-chloro-3- trifluoromethylphenyl)-1,4-dihydro-5-isobutoxy-2-methyl-l,6- naphthyridine-3-carboxylate • dihydrochloride m.p. >140 *C (decomp.) from diisopropylether/acetonitrile lbt.) (N-benzyl-3-pyrrolidinylmethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate m.p. 125-128 *C from diisopropylether lbu.) Ethyl-(+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate m.p. 130-131 *C from n-hexane » 22 86 22 lbv.) Ethyl-(-)-l,4-dihydro-5-isopropoxy-2-methyl-4-(2-trif luoromethylphenyl) -1,6-naphthyridine-3-carboxylate m.p. 130-131 "C from n-hexane lbw.) [ 2- (N-benzyl-N-methylamino) ethyl ] - (+) -1,4 -dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • dihydrochloride m.p. >137 *C (decomp.) from ether lbx.) [2-(N-benzyl-N-methylamino)ethyl]—(-) -1,4-dihydro-S-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate • dihydrochloride m.p. >136 *C (decomp.) from ether lby.) (2-Trimethylammonioethyl) - (±) -l,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate iodide m.p. 149-150 *C from ethanol 228622 Example 2.

Methyl (—)-l, 4— dihvdro-5-methoxy- 2-methyl-4— phenyl— 1,6-naphthyridine-3-carboxvlate. g. (17 mMol) Methyl (i)-l,4,5,6-tetrahydro-2-methyl-5-oxo-4—phenyl-1,6-naphthyridine-3-carboxylate 10 and 5 g. (34 mMol) trimethyloxonium tetrafluoroborate in 200 ml. 1,2-dichloroethane are stirred for 1.5 hours at ambient temperature under an atmosphere of nitrogen. The reaction mixture is shaken out with 50 ml. water and the organic phase is separated off and evaporated 15 on a rotary evaporator. After recrystallisation of the residue from isopropanol, there is obtained the tetra-fluoroborate of the desired compound. This is stirred vdth a saturated aqueous solution of potassium hydrogen carbonate and diethyl ether and the ethereal solution 20 is separated off, dried over anhydrous sodium sulphate and evaporated on a rotary evaporator. Crystallisation of the free base from 50 ml. n-hexane/diisopropyl ether (2:1 v/v) gives colourless crystals: m.p. 210 -212°C.

The methyl (- )-l,4,5,6-tetrahydro-2-methyl-5-oxo— 4-phenyl-l,6-naphthyridine-3-carboxylate used as starting material is prepared analogously to Example 1 vdth 22 8 6 2 the use of methyl 1,4-dihydro-2, 6-dimethyl-4—phenyl-pyridine- 3,5-dicarboxylate.

The following compounds are obtained in an analogous manner: ethyl (—)-4—(2-chlorophenvl)-l,4-dihvdro-5-methoxv-2-methyl-1,6-naphthvridine-3-carboxylate (2.a); m.p. 173 — 174°C. , recrystallised from n-hexane/diisopropyl ether ethyl (-)-l,4—dihvdro—5-methoxv-2-methvl-4— (3-nitrophenyl )-l,6-naphthyridine-3-carboxvlate (2.b); m.p. 184 - 186°C., recrystallised from diisopropyl ether/ ethanol ethyl f- )-4- ( 2—fluorophenyl )-l. 4—dihydro-5-methoxv-2-methyl-1,6-naphthvridine-3-carboxvlate (2.c); m.p. 148 — 150°C., recrystallised from n-hexane ethyl (-)-l. 4—dihvdro-5-methoxv-2-me thvl-4- ( 2-trifluoromethylphenyl)-l,6-naphthyridine-3-carboxvlate (2.d); m.p. 118 - 120°C., recrystallised from n-hexane methyl (—)-4—(3-chloro-2—fluorophenyl)-1.4-dihydro-5-methoxy-2-methyl—1,6-naphthyridine-3-carboxylate (2.e); m.p. 214 - 216°C., recrystallised from diisopropyl ether/me thanol methyl ( — )-4— ( 2—bromophenyl )-l ,4— dihydro-5—methoxy—2— methyl-l.6-naphthvridine-3-carboxvlate (2.f); m.p. 204 - 205°C. , recrystallised from diisopropyl ether/ methanol 22 8 6 2 2 Example 3. (- )-l,4-Dihvdro—5-isopropoxy-2-methvl-4-(2-trif luoromethvlphenyl )-l.6-naphthyridine-3-carboxylic acid. 3.0 g. (6.2 mMol) Benzyl )-l,4— dihydro-5-isopropoxy-2-methyl-4—(2-trifluoromethylphenyl)-l. 6— naphthyridine-3-carboxylate are hydrogenated at normal pressure and at ambient temperature with the use of 1.5 g. 10% palladium on active charcoal in 100 ml. ethanol. The take up of hydrogen is finished after 30 minutes. The catalyst is filtered off, the solvent is distilled off in a vacuum and the colourless, crystalline residue is recrystallised from diisopropyl ether/ethyl acetate. There is obtained (-)-l,4-dihydro-5-isopropoxy- 2-methyl—4— (2-trif luoromethylphenyl )-l, 6-naphthyridine- 3-carboxylic acid in the form of colourless crystals with a melting point of 164 - 166°C. (decomp.).

The benzyl (i)-l,4-dihydro-5-isopropoxy-2-methyl— 4-(2-trifluoromethylphenyl)-1,6-naphthyri dine-3-carboxylate used as starting material is prepared analogously to Example 1 with the use of dibenzyl 1,4-dihydro-2,6-dimethyl-4—(2-trifluoromethylphenyl)-pyridine-3,5-dicarboxylate.

The following comparative experiments demonstrate the pharmacologically effectiveness of the compounds of general formula (I): a) Isolated smooth muscle.

Isolated smooth muscle from rabbits (blood vessel 22 8 6 2 2 rings, A. basilaris, A. coronaria, A. saphena) are fixed in an organ bath in such a manner that isometric contractions can be measured. The contraction is initiated by a potassium depolarisation in tyrode solution. The experimental protocol is a known standard model for the recognition of compounds which block the calcium canals opened in the potassium depolarisation (Fleckenstein, 1983). As can be seen from the following Table I, some substances act semi-maximally relaxingly in the nanomolar range. In part, this potency considerably exceeded that of the already known calcium antagonists diltiazem and nifedipine. b) Isolated papillary muscle.

Papillary muscle from the left ventricle of the guinea pig is fixed, as in the case of isolated vessels, in an organ bath for isometric contraction measurement and electrically stimulated by field stimulation with a frequency of 250/min. (stimulation period 10 msec., amplitude supramaximal). The following Table II shows that the compounds display their calcium antagonist action selectively on the smooth vessel muscle and on the myocardium show surprisingly, in the therapeutic range (1-100 nmolar) no negative but in part even positive inotropic action. However, it can not be excluded that the dimethyl sulfoxide used as a solvent has contributed to the observed positive inotropic action. The compound of Example 1c) possess, at a 22 8 6 -7 therapeutic concentration of 3 x 10 mol/litre, a maximum increase of the contractility of 36 % and at -9 a concentration of 4 x 10 mol/litre, this is + 18 % 22 8 6 22 Example 4 (see compound 1.1) /d ro-5^--Ls_Q-P.r Q£Q^yr2 -tne_tiiy-L^'L-2( -1 rxXI u.or_Q- 1. 3 £ C 3 mMol) sodium hydride (80 X in paraffin oil) are suspended in 200 ml dry dimethylformamide and 12. 5 £ ( 33 mMol) et hyl ( a) -1, 1, 5, 6-tetrahydro-2-methyl-5-oxo-i)-( 2-tri fl uoromethyl-phenyl)-1, 6-naphthyridine-3-carboxylate is added in portions thereto at ambient temperature, while stirring. After cessation of the evolution of gas, the reaction mixture is further stirred for 15 minutes at ambient temperature. 7.2 £ ( 43 mHol) isopropyl iodide is than added. Stirring is continued for 3 days at ambient temperature. The solvent is evaporated off in vacuo and after adding of 500 ml water the residue is treated in the ultrasonic bath for 30 minutes. The resulting crystalline mass is filtered off and dried at 50 °C.

For purification of the crude product, it is solved in ethyl acetate and chromatographed over silica gel with toluene / ethyl acetate (3 : 1 v/v). The solvent of the fractions of R» 0, H is evaporated in vacuo and the residue is stirred till crystallization with n-hexane. The product is filtered off and recrystallized from 60 ml n-hexane. Colourles crystals are obtained, m. pt. 102-103 °C.

The ethyl ( ±)-1, t, 5 , 6-tetrahydro-2-methyl-5-oxo-1-( 2-1rif1uoro-methylphenyl)-1, 6-naphthyridine-3-carboxylate used as starting material is prepared as follows: A solution of 79.2 g ( 0. 2 Mol) diethyl 1,4-dihydro-2, 6 dimethyl-t-( 2-trifluoromethylphenyl) pyridin-3, 5-dicarboxylate in 400 ml dimethylformamide is added dropwise, under an atmosphere of nitrogen, to a suspension of 6.0 g ( 0. 2 Mol) sodium hydride (80 % in paraffin oil) in 100 ml dry dimethylformamide. Upon slowing down of the evolution of gas, the reaction mixture is further stirred for 10 minutes at ambient temperature and subsequently 16.2 g (0.2 Mol) s-tria2ine in 300 ml di me t hyl f ormami de are added dropwise thereto. The reaction mixture is heated to 110 °C 2 2 8 6 2 2 for 16 hours under stirring and. after coolini, evaporated in a vacuum. The residue is stirred with 1.5 1 acetone, filtered and the filtrate evaporated in a vacuum. The residue is chromatographed o'.vr silica £el with d i c hi or omo t ha ne ' methanol (9 : 1 v/v). The fraction with P« 0.45 is stirred with 200 ml chloroform and the pale bei£e crystals are filtered off. For further purification they are recrystallized form ethanol and colourless crystalr. are obtained, m. pt. 261 "C.

The diethyl 1,4-dihydro-2,6-dimothyl-^-(2-trifluoromethyl-phenyl) pyridin-3. 5-dicarboxylate used as starting material is prepared as follows: 50 g (0.29 Mol) 2-1rif1uoromethyl benzaldehyde and 76 g C0. 58 Mol) ethyl acetoacetate in 30 ml aqueous ammonia are boiled for 16 hours with 200 ml ethanol. The product, precipitated after cooling, is filtered off and washed with cold ethanol. Pale beige crystals are obtained, m. pt. 142-143 °C. 22 8 62 TABLE I Table I shews concentrations (IC^q, mol/1.) of ccnpounds (I) which bring about a semi-maximum inhibition of the K-1" depolarisation contraction of blood vessel rings in an organ bath. For comparison, there is given the ICgQ values of the calcium antagonists diltiazein and nifedipine. ! compound of j Example No. 1 A. bas. ^ 1 2 A. cor. i 2 A. saph. 1 i x 10~9 3 x 10~8 7 x 10~9 la 2.4 x 10~9 2.7 x 10~9 8 x 10"9 lh 3 x 10"6 1.5 x 10"8 1 x 10~6 lb 6.6 x 10"10 7.5 x 10"10 3.4 x 10~9 1c 1.5 x 10"8 6.5 x 10"8 1 x 10~6 ig .9 x 10~9 3.2 x 10"9 — n 7.4 x 10~9 3.1 x 10"8 3.9 x 10~7 ip 1.6 x 10~8 .3 x 10~8 — 00 1 o H X ir> • cn 1.9 x 10~7 — 2 2.5 x 10~7 1 x 10"5 9 x 10~8 2a 6 x 10"9 1 x 10"8 6 x 10"7 2b 1.8 x 10~9 1.2 x 10~8 6 x 10"7 diltiazem nifedipine 1.2 x 10"7 2.7 x 10~9 1.7 x 10~7 5 x 10~9 2.9 x 10"6 5.9 x 10"8 1. A. bas. = arteria basilaris ) 0 . . ? obtained from rabbits: 2. A. cor. ss arteria coronarxa ) ) average diameter 0.5 — 3. A. saph. = arteria saphena ) mm. 228622 TABLE II Changes of the contraction amplitude of isolated papillary muscle of the guinea pig (stimulation frequency 250/min., stimulation time 10 msec., stimulation amplitude 10-20 V field stimulation). IC = inhibiting concentration, IC^qq corresponds to maximum action. = maximum decrease of the con tractility. The inhibiting concentrations of diltiazem and nifedipine are given for coirparison. compound of Exanple No. number of animals IC100 ; A % 1 (n=7) 3.10"4 -40 1 la (n=4) 3.10"4 -48 lh l.io*4 -38 11 1.2.10"4 -38 1.10"5 -23 iq 1.10"5 - 7 lh (n=4) 3.10~4 i -54 i diltiazem (n=6) "5 -60 nifedipine * io-6 -80 *Hof and Scholtysik, J. Cardiovasc. Pharmacol. 176-183/1983), Experiments on the papillary muscle of the rabbit. 22 8 6 2 2 Table II shows the maximum actions on the contractility in the case of the concentrations necessary herefor (IC 100 = inhibitory concentration). From this, it can be seen that the comparison compounds, 5 even in the case of considerably lower concentrations (IC 100), show a higher decrease of the contractility. The concentration IC 100 lies far outside of the therapeutic range of the compounds according to the present invention so that a negative inotropism is 10 there not to be found. It follows from this that the therapeutic safety of the compounds according to the present invention is considerably increased in comparison with the prior art. 22802- 36

Claims (42)

WHAT WE CLAIM IS:

1. The compound (±)-1.4-Dihyaro-5-isopropoxy-2-metnyi-4-(2-tri fluoromethylphenyl) -1 .6-naphthyrida ne-3-carboxy lie acid-(2-aminoethy1)-ester.

dihydro-5-isopropoxy-2-metny1-1.6-naphthyr:d:ne-3-carooxyllc acid ethyl ester.

3. A compound ti)-i,4-Dihydro-5-isopropoxy-2-metnyi—4-(2.3-methy1en-dioxy-pneny1)-1.6-naphthyridine-3-carboxylic acid ethyl ester.

4. A compound ( ± )-1 .4-Dihydro-5-isopropoxy-2-rnethy 1-4- ( 2—

trl f luoromethy 1 -pheny 1 ; -1 . 6-naphthyr iai ne-3-car.boxy 1 ic acid- ( 2 piperidino-ethy1) ester.

5. A compound (± J —4 — C 2—Ch1oropheny1 —1.4—aihydro—5-isopropoxy 2-methyl-l.6-naphthyridine-3-carboxy1ic acid ethyl ester.

6. A compound (±)-1.4-Dihydro-5-isopropoxy-2-methy1-4-pheny1 1,6-naphthyridine-3-carboxy1ic acid ethyi ester.

7. A compound (±)-1,4-Dihydro-5-isopropoxy-2—methyl-4—(2-trifluoromethy1—phenyl)-1.6-naphthyridine—3-carboxy1ic acid-[3

2. The compound (±)-4-(2-Dif1uoromethy1thiopneny1)-1.4-

22862°

37

(N-benzyl-N-methylamino) propyl ] ester . dihydrocruoriae .

8. A compound (4R3)-1 . 4-Dihyaro-5-isopropoxy~2-;nethy i-4- ( 2-

tr i f 1uoromethy1-phenyi) — 1.6-naphtnyradine-3-carboxy1ic acid-(R)-2-butylester.

9. A compound (4RS)-5-[(RS)-Sec-butoxyJ-1.4-dihyaro-2-metnyl 4-(2-trifluoro-methy 1pneny1) — 1.6-naphthyridine-3-carboxylic acid-(2-N-benzyi-N-metnylamino)etnyl]ester • aihyarocnioride.

10. A compound (±)-1.4-Dihydro-b—methoxy-2-methy1-4(2-

trif1uoromethy1pneny1)-1.6-naphthyrldine-3-carooxy1ic acid-(2-dimethylaminoethy1) ester.

11. A compound ethy1-(+)-4—(2.1,3-benzoxadiazo1-4-y1)-1.4-dihydro-5-isopropoxy-2-methyl-l,6-naphthyridine-3-carboxylate.

12. A compound N-benzy1-3-piperidiny1-(±)-1.4-dihydro-5-isopropoxy-2-methy1-4-(2-tri f1uoromethy1pheny1)-l.6-naphthyridine-3-carboxylate.

13. A compound N-benzy1-4-piperidinyl-(±)-1.4-dihydro-5-isopropoxy-2—methy1-4-(2-trifluoromethy1pheny1)-1.6-naphthyridine-3-carboxylate • sesquiphosphate.

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36

14. A compouna [ 2- ( N, N—dibenzy 1 ammo ) ethy 1 J - ( ± ) 1. 4-di hydrc-5-

r isopropoxy-2-methy 1 -4- ( 2-tr ife-1 uoromethy 1 p.neny 1 ) -1.6-naphthyr idme-3-carboxy late • sesquiphospnate .

15. A compouna I 2- (N-met hy 1 -N-pneny i ami no) etny 1 j -(♦.)-1 . 4-dihydro-5-isopropoxy-2-methy1-4-(2-trir1uoromethy1pheny1}-1.6-naphthyrida ne-3-carboxy1 ate.

16. A compound ethy1-(z)-4-(2~chloro-3~

tri f 1 uoromethy 1 pheny 1 ) -1. 4-di hydro-i5-isopropoxy-2-metny 1-1, 6-napht"nyridine-3-carboxy late,

17. A compound (2-(N.N-d2ethylamino)ethy1]-c±)-1.4-dihydro-5-isopropoxy-2-metny1-4-(2-trif luoromethy1pheny1)-1.o-naphthyridine-3-carboxy1 ate hydrochloride.

18. A compound ethyl-(±)—l,4-dihydro-5-isopropoxy—2-methyl-4-(3-tri fluoromethy1 phenyl)—1,6—naphthyridine—3-carboxylate.

19. A compound ethyl-(±)-l.4—dihydro-5-isopropoxy-2-methy1-4-(4-trifluoromethylphenyl)-1. 6—naphthyndine-3-carboxylate.

20. A compound ethy1-(±)-1,4-dihydro—5-isopropoxy-2-methy1—4— (2—pyridy1)-1,6—naphthyridi ne-3-carboxy1 ate .

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21. A compound ethy1-(♦)-1.4-aihydro-5-ethoxy-2-methy1-4-(2-trifluoromethy1pheny1)-1.6-naphthyrida ne-3-carboxylace.

22. A compound ethy 1-{r)-1.4-dihydro-2-me thy 1-5-propoxy-4-(2-tri f 1uoromethy1pheny1)-1.6-naphthyridine-3-carboxylate.

23. A compound (2-(N-benzy1—N-methy1 ami no)etny1]-(±)-4-(2-chloro-3-tri f1uoromethy1pheny1)-1.4-dihydro-5-isopropoxy-2-methy1—1.6—naphthyridine-3-carboxy1 ate • dihydrochloride.

24. A compound (2-(N-benzy1-N-metny1 ami no)ethy1)-(±)-1.4-dihydro-5-isobutoxy-2-methy1-4-(2-tribluoromethy1pheny1)-1,6-naphthyridine-3-carboxylate • dinydrochloride.

25. A compound [2-(N-benzy1-N-methy1 ami no)ethy1]-(±)-4-(2-cyanophenyl)-1,4—dihydro-5-isopropoxy-2-methy1-1.6-naphthyridine—3-carboxylate.

26. A compound (2-Phenoxyethyl}-(±)-1.4-dihydro-5-isopropoxy-2-methyl-4-(2-tri r1uoromethy1pheny1)-1,6-naphthyridine-3-carboxylate • sesquioxalate.

27. A compound [2-(N-benzy1-N-methy1amino)ethyl J -(±)-1,4-dihydro—5-methoxy—2-methyl-4-(2—tri f1uoromethy1phenyl)-1.6— naphthyridine-3-carboxylate • sesquioxalate. _ .

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28. A compouna methy 1 - ( + ) -4-( 2 . 6-d ich 1 crcpheny 1 )-i . 4-dihyaro-5-isopropoxy-2-methy 1 -1. 6-naphtftyr idi ne-3-car boxy lace.

29. A compound (2-phenoxyethy1)-(±)-1.4-cihyaro-5-isobutoxy-2-methy1-4-(2-tr irluoromethy1pneny1)-1.6-naphtnyridine-3-carboxylate • hydrobromide.

30. A compound (2-phenoxyethy1)-4-(2-dif1uoromethoxypheny1)-1.4-dihydro-5-isopropoxy—2-methyl-l.6-naphthyridine-3-carboxylate.

31. A compound benzyl-(±)-1.4-dinydro1—d-isopropoxy-2-metny1-4-(3-nitrophenyl)-1.6-naphthyridine-3-carboxylate.

32. A compound cyclopropyimethy1-(+)-1.4-ainydro-b-isopropoxy-2—methy1-4-(2-trif1uoromethy1pheny1)-1.6-naphthyridine-3-carboxylate.

33. A compound ethy1-(±)-1.4-dihydro-5-isopropoxy-2-methyl-4-(3—nitropheny1)-1.6-naphthyrid ine-3-carboxylate.

34. A compound (trans-cinnamy1)-(±)-1,4-dihydro-5-isopropoxy-2-methy1-4—(2-trif1uoromethy1pheny1)-1.6-naphthyridine-3-carboxylate • sesquioxalate.

35. A compound [2—(N-benzy1—N-mechylamino)ethyI]-(*)-4-(2-chloro-3-tri fluoromethy1pheny i)—1,4-dinyaro-5-isooutoxy-2-methyl-1. 6-naphthyridme-3-carboxy late • dinydrochlonae.

36. A compound (N-benzyi-3-pyrrolidinyImethyl)-(t)-1.4-dihydro-5—isopropoxy-2-methy1-4-(3-n itropheny13-1.6-naphthyridine-3-carboxylate.

37. A compound ethy1-( +3-1.4-dihydro-5—isopropoxy-2-methy1 (2-tri f1uoromethy1 phenyl)-1,6-naphthyricu ne-3-carcoxylate.

38. A compound et hy1-(-;-1.4—da hydro-5-isopropoxy-2-methyl (2-trir"luoromethy 1 pneny 1 J -1, 6-naphthyridme-3-carboxylate .

39. A compound [ 2-(N-benzy 1 -N—me thy lami no 3 ethy 1J - (+ )-1 .-4-dihydro-5-isopropoxy—2-methyl-4-(2-tri f1uoromethy1 phenyl(-1 naphthyridine-3—carboxylate • dihydrochloride.

40. A compound [ 2- (N-benzy 1 -N-metht-ylammo) ethy 1 ]-(-)-1, 4-dihydro-5-isopropoxy-2-methy1-4-(2-trif1uoromethy1pneny13-1 naphthyridine-3-carboxy1 ate • dihydrochloride.

41. A compound ( 2-tr imethy lammonioethy 13 — (± 3-'l,4-dihydro-5-

isopropoxy-2-methyl—4— (3-nitrophenyl 3 -1 . 6-naR3T£fry3&idine-3-

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carboxylate loaide.

42. A pharmaceut1ca1 composition containing at least one of the compounds or" claims 1 to 41 in admixture witn a solid or liquid pharmaceutical diluent or carrier.

GODECKE AKTI ENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By:

I -4 AUG 1939 vJ

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