IL85289A - Alkyl-substituted n-benzopyranyllactams, a process for their preparation, their use, and pharmaceutical preparations based on these compounds - Google Patents

Description

ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAMS, A PROCESS FOR THEIR PREPARATION, THEI R USE, AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS n ¾> D ooi-.nn mnpn n>eom ona I HOECHST A TIENGESELLSCHAFT D .vF/gm HOE 87/F 028 Description Alky I -subs t i tuted N-benzopy r any L I ac tarns, a process for their preparation, their use, and pharmaceutical preparations based on these compounds The invention relates to N-benzopyranyl lactams of the formula I i n wh i c h R1 represents CN, O2, SOn-(Ci-C0)-alkyl or SOn-Ar; where n = 1 or 2, Ar represents an aro- . -^Mn t.rc'-or :iiBt¾r.O rom t ic ^s st^m ί-h cti is unsubs t i- tuted or substituted by 1 to 3 identical or different ( C i-C2>-alky I, (C<|-C2>alkoxy, halogen, tr if luoromethyl, CN, Og, C0-( C-alkyl or S0p-(Ci-C )alkyl radicals, and p represents 1 or 2, 2 R represents H, OH, (C-j-Cj -alkoxy, (C1-C - alkyl, halogen or NR5R6, where R^ and R6 are identical or different and represent H, (C1-C2 - alkyl or (C-¾-C2)-alkylcarbonyl , R^ and R^ are ide/itical or different and represent alkyl having 1-4 carbon atoms, the abovement oned meanings of 1 and 2 R R may also be exchanged, and X represents a (CH2>m chain which is substituted by at least 1 and at most 2m-1 (C<|-C2)-alk l grOUpS anrf-may fra pfta r r■.p a A hy a ha fa r r. a n m V Ha, -xua-ting 0j N ^ OP G, and ^ "represents H o ^ (C ^--C- )-"al-k-y?> and m represents 2, 3 or 4, where the conf gurations at C3 and C4 are always opposed.

An aromatic system Ar is preferably taken to moan- phenyl naphthyl or biphenylyl, and a 5- or 6-membered hetero-aromatic system Ar is -preferabl - a radical of a 5- or 6-membered 0-, N- and/or S-heterocycl ic ring, selected from f u ry I , t h i eny I , isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl.

Halogen is taken to mean F, CI, Br or I, preferably F and CI.

Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzoCb]pyran system (called "chroman .system" below) of the formula I are asymmetrically substituted. The invention relates only to those compounds which have opposed configurations at these centers. This means that the lactam ring as a substituent on C-4 and the OH group on C-3 are always oriented "trans" to one another. The abovement i oned definition of X means that, in addition, the lactam ring contains at astsΛtie/:;ibirt¾::a tisifl-s t : .t«h:eT.e-m -*as ÷the definition mentioned initially) chiral carbon atoms. In this case, the invention relates both to compounds having - and S-configured centers. The same applies in the 1 2 3 4 case where R , R , R or R contains centers of asy -metry or produces a center of asymmetry even as a substituent. The compounds can then exist as optical isomers, as diastereoisomers, as racemates or as mixtures thereof.

Preferred compounds of the formula I are those in which R , R , R and have the abovement i oned meanings and X represents a (CH2 m chain which is substituted by a (Ci-C2 -alkyl group .and moy be interrupted by a1 hetaroatam Y which represents 0, S or NR^ where •denotes H or—(C^C-j-alk l1, and where m represents 2, 3 or 4.

Additionally preferred compounds of the formula I are those in which R^ to ^ have the abovement i oned meanings and X represents a (CH2 m chain which is substituted by a ( C -J -C.2 ) -a I k y I group and where m represents 3 or 4.

Very particularly preferred compounds I are those in 1 4 which R to R have the abo vemen t i oned meanings and X represents a (CH2)m chain where m represents 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C-j-C^alk l group.

Especially preferred compounds are those in which R - R have the abovemen t i oned meanings and X represents a ( H2 m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a ( C -j-Cg ) -al ky I group, namely in a fashion such that the conf iguration of this carbon atom is the same as that of the C-4 atom of the chroman system. those in which 1 2 R represents CN or SO -CH3 and R represents H, 3 4 R and R are identical or different and represent alkyl having 1 or 2 carbon atoms, X represents a C C H2 ) m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom in the lactam ring by a (C-j-C2>-alkyl group, namely in a fashion such that the conf iguration of this carbon atom is the same as that of the C-4 atom in the chroman system; especially preferred compounds I are those in which represents S0 _Ar where Ar denotes phenyl which is unsubst i tuted or substituted as mentioned above by 1 to 3 subst i tuents, represents H or OCH3, and R are identical or different and represent (Cf-C2)-alkyl, and X represents a (CH m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the Lactam ring by a (C1-C2)- aLkyl group, namely in a fashion such that the configuration of this carbon atom is the same as that of the C-4 atom in the chroman system. 1 4 Preferred compounds are also those in which R -R have the abovement ioned meanings and X represents a ( H2>m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (Ci~C2)-alkyl group, namely in a fashion such that the configuration of this carbon atom is opposite to that of the C-4 atom of the chroman system.

Likewise very particularly preferred compounds I are those in wh i ch R^ represents CN or SO2-CH3 and R^ represents H, R3 and R4 are identical or different and represent alkyl having 1 or 2 carbon atoms, X represents a ( H m chain where m = 3 or 4 and uhic i s.¾ubs:t*tJUted on; .tbe ·£ axb.aj .-a.t-o.m me..i:ghbor.mg .t he nitrogen atom in the lactam ring by a ( C 1 -C2 ) -a I ky I group, namely in a fashion such that the configuration of this carbon atom is opposite to that of the C-4 atom in the chroman system; especially preferred compounds I are those in which 1 R represents S0 _Ar where Ar denotes phenyl which is unsubst i tuted or substituted as mentioned above by 1 to 3 subs t tuents , R^ represents H or OCH3, 3 4 R and R are identical or different and represent (C-j-C2)-alkyl, and X represents a (CH2)m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C^-Cg)- alkyl group, namely in a fashion such that the configuration of this carbon atom is opposite to that of the C-4 atom in the chroman system.

Compounds very similar to the compounds according to the invention are described in J. Med. Chem. 1986, 29, 2194- 2201. They are summarized there under the following general formulae: · where R 1, R2, R3, Z, n, m and R have the meanings specified therein. The majority of these compounds is also described in various patent applications, of which oned: EP 107,423, EP 120,427, It is known of these compounds that they are capable of reducing blood pressure which has been increased in the course of a disease, by relaxing the smooth vascular muscles or protecting them or rendering them insensitive to pressor stimuli.

In the compounds of the formula I according to the invention, a new class of substances has now been found which has blood pressure-reduc ng properties and which differs from the known compounds above all by the fact that they carry additional subst ituents, as defined above, in the lactam ring as a substituent on C-4 of the chrontan system.

Compared to the previously known unsubst ituted compound, this substitution Leads to a considerabLe increase in the additionaL antihypertensive action. In addition, it has been observed that, in some cases, such an increase in action is accompanied by a reduction in the acute toxicity, which overaLL resuLts in an improvement in the therapeutic range. This is of utmost importance preciseLy in Long- term therapy, such as the treatment of hypertonia, where it is in some cases necessary for a medicament to be taken for Life. 10 The steric requirements which Lead to this type of advantageous profiLe require further explanation. In the literature cited above, it was possible to show that the substituents on C-3 and C-4 must be arranged in the trans- 15 position to one another for an optimum antihypertens ve action. In contrast, a c i s -a r r angemen t Leads to a significant weakening of the effect. Such trans-conf gures compounds also occur in the form of antipodes. It was possible to show, with reference to an example, that the •2 ·., .;< - >r*aat-I.R de ^tias f ;a..rfca r-¾:tTHO:ngeT,v;arctd n.;?^:a ^fie"--.{ + ) - antipode. The (-)-antipode was in this case assigned the 4R, 3S-conf igurat ion (cf. EP 0,120,428).

By introducing substituents into the Lactam ring in ac-25 cordance with formula I, further additional centers of asymmetry are produced. The compounds according to the invention can then occur not only as antipodes, but the additional appearance of diastereoisomers, which, although having an identical constitutional formula, can readily be 30 different ated by means of common spectroscopic or chromatographic methods, is observed. The configuration of a new center of asymmetry in the lactam ring can be identical or opposed with respect to the configuration of C-4 in the chroman system, for example. If it is identical, it is 35 opposed with respect to the conf guration at C-3; if it is opposed, it is identical with respect to C-3. These two relative arrangements of a certain configuration in the Lactam ring with respect to the trans configuration of the chroman system are manifested in two diastereoisomer ic compounds of the formula I. Surpris ngl ,, the above-mentioned advantageous properties of the compounds I can in many cases only be observed for one of the two diastereo-isomers, while the other is substant all less active than the corresponding unsubs t i tuted compound. These are preferably compounds I which carry an alkyl substitutent on the lactam carbon atom neighboring the lactam nitrogen and whose relative conf guration is identical to that of the C-4 atom in the chroman system.

The introduction of substitutents nto the lactam ring in accordance with formula I thus does not always lead, as would be expected, to a useful antihypertensive activity, but a very specific spatial orientation of these substituents relative to the centers of asymmetry which are already present must be maintained. Some of the compounds of the formula I also differ from the previously known compounds by the fact that they additionally carry an aryl sulfonyl or aryl sulfoxy substituent as substi-tuen.t s :i thfi¾ean i ng mentioned initially. It was hitherto not known that this type of substitution can also lead to this antihypertensive activity.

In addition, some of the compounds according to the invention, in particular those diastereoisomers which, as mentioned above, have less pronounced cardiac circulation effects, exhibit a strong relaxant action on the ureter. Such compounds I are thus valuable therapeutic agents in the treatment of renal cholic and in lithotriptic treatment. In both cases, a relaxant effect on the ureter eases passage of stones.

The invention furthermore relates to a process for the preparation of the compounds I, wherein a) compounds of the formula II in which R , R , R and R have the abovementioned meanings, are reacted with Lactams of the formula III compounds of the formula in which R , R , meanings, are reacted «i th lactams of ..tJie .formula III , or c) compounds of the formula V in which R , R , R and R have the abovement meanings, are acylated to give the compounds VI in which R to R and X are as defined above and Y denotes a leaving group such as chlorine or bromine, and the latter are cyclized to give the compounds I, or d ) compounds of the formula VII in which R to R and X are defined as above, 10 are ox dized to give the compounds I.

If the compounds I are prepared by methods a) or b), this preparation takes place by reacting the compounds IV or II with the lactams III in a suitable solvent, preferably 15 in dipolar aprotic solvents, such as dimethyl sulfoxide or THF, preferably with the involvement of bases, such as sodium hydride, potassium t e r t-buty I a te or similar bases which are known to be suitable for lactam N-a I ky I a t i ons .

The reaction temperature in this reaction can be varied ;20. :.wi-th in .a brriad - -ange, and the reaction is preferably carried out between 0°C and room temperature. When racemic or optically uniform lactams III are used, at least two new products of the formula I are obtained. These products can be separated by conventional methods, such as 25 crystallization or chromatography; a combination of the two methods has also proved favorable in many cases. The particular overall configuration can then be allocated to each product by means of common physical investigations, such as, for example, X-ray structural analysis or NMR 30 spectroscopy. Optically uniform, i.e. enan t i ome r i c a 11 pure compounds I can be obtained by subsequent racemate resolution. However, if lactams III which are already enant iomer i cal ly pure are used, the d as tereo i some r c compounds I are likewise obtained in enant iomer ical ly pure 35 form and racemate resolution becomes superfluous.

Lactams of the formula III are in many cases known or can easily be prepared by methods which are known from the literature. The bromohydrins II and the epoxides IV are in many cases Likewise known (in this respect, cf. the patent specifications cited above or J. Med. Chem. 1986, 29, 2194-2201) or can be prepared analogously to the methods given therein. Hitherto unknown are compounds II and IV in which R represents -SOn-Ar where n and Ar have the abovement i oned meanings. They can be prepared, for example, according to the following equation: 2,3-d i hydro-2H-benzo[b]p r an-4-ones of the formula VIII are reacted with acid chlorides Ar-S02~Cl in a fashion which is known per se in the manner of the F r i ede I -C r a f t s acylation, to give compounds of the formula IX in and n are as def R4 are as defined above. These compounds IX are converted through reductions under standard conditions, such as by means of NaBH in methanol, into compounds X and the latter are subsequently subjected to elimination of water, for example by means of pyr idine/phosphorus oxychloride, giving 2H-benzoCb]py renes of the formula XI Compounds XI can easily be converted by standard methods into the epoxides IV or the bromohydrins II. If, in this 2 reaction sequence, R denotes NH or OH, protecting groups, such as, for example, the dimethylaminomethylene group for NH2 or the acetyl or methyl group for the OH group, may be necessary. These are removed again by common methods at suitable stages, preferably after carrying out the reactions described in process a) or b).

As stated above, the compounds of the formula I according to the invention are antih pertensi es which can be employed as pharmaceuticals in human and veterinary medicine. They are administered enterally, for example orally or parenterally (such as, for example, by injection into the vascular system, for example intravenousl ), in the form of capsules, coated tablets, tablets, powders, suppositories or solutions with additives or without additives of galenic adjuvants in dosages of at least 0.001 mg/kg/ day, preferably 0.005 mg and in particular 0.55 mg/kg/day to a maximum of 10 mg/kg/day, preferably 5 mg/kg/day and in particular 2 mg/kg/day, in each case relative to a weight :0 f - abou-t -J5 g i, ';-T:h -tab t-e , .o ---i-fcraaime n t .io f ypertonia, alone or in combination with other antihypertensive medicaments, such as, for example, diuretics, Ca antagonists or ACE inhibitors. These data relate to a human weighing 75 kg.

Exaaple 1 (3R*, 4S*, 5'5*)-6^3ηο-3,4^ΐί^Γθ-2,2^ιπΐθ^Ι- -[:2·-oxo-5,-methyl-1-pyrrol dinyl)-2H-ben2oCb]pyran-3-ol and (3R*, 4S*, 5'R*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-C2'-oxo-5,-methyl-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol. 3.6 g (0.12 mol) of 80 X NaH (suspension in oil) are introduced into a solution of 32 g (0.113 mol) of 6-cyano-trans-3-bromo-3,4-d hydro-2,2-dimethyl-2H-benzoCb]pyran-4-ol in 200 ml of DMS0 at 20°. After stirring for one hour, a further 4.8 g (0.16 mol) of 80 % NaH and 15.9 g (0.16 mol) of racemic 5-methyl-2-pyr rol done are introduced. After stirring overnight at 20° the reaction mixture is poured into ice water, and the precipitate is rec ry s t a L L i zed from methanol.

The rec rys ta L I i zed mixture is separated on a silica gel column using CH2C12/CH30H (95:5). (3R*, 4S*, 5'S*)- 6-cyano-3, 4-dihydro-2, 2-dimethyl-4-C2' -oxo-5 ' -methyl-1'-pyrrol idinyl D-2H-benzo[b]py ran-3-ol is isolated and re-crystallized repeatedly from ethanol.

Crystals of melting point: 239-240° N R (d6-DMS0) CH3 signals S 0.80 (3H, d) 1.17 (3H, s) 1.45 (3H, s) Analysis: calculated for <|7H20N2°3 : 300.37 calc. C, 67.98; H, 6.71; N, 9.33 % found C, 67.9; H, 6.8; N, 9.4 % The methanolic mother liquor, in which (3R*, 4S*, 5'R*)-6-c mo 3> 4-d h ydr o-2;,Z - di me th y.i-4-Γ.2 '-r-oxo-5 · ruei h y I- 1 ' -pyrrol idinyl ) -2H-benzoCb]py r an-3-ol is concentrated, is evaporated, and the compound is isolated on a silica gel column using CH2 I2 CH3OH (95:5).

Crystals of melting point: 190-192° (from ethyl acetate) NMR (d6-DMS0) CH3 signals S 1.20 (3H, s) 1.30 (1.5H, s) 1.43 (4.5H, s) Analysis: calculated for Ci7H20N2°3: 300.37 calc. C, 67.98; H, 6.71; N, 9.33 % found C, 68.0; H, 6.7; N, 9.4 % Exaaple 2 (-)-(3S, 4R, 5,R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-C2' ox0-5' -methyl-1 -pyrrol dinyl )-2H-benzoCb]pyran-3-ol and (-)-(3R, 4S, 5,R)-6-cyano-3,4-dihydro-2 2-dimethyl-4-C2' oxo-5' -methyl-1-pyrrol idinyl )-2H-benzoCb]pyran-3-ol 6 g (0.2 mol) of 80 % NaH and 15 g (0.15 mol) of (R)-5-methy l-2-py r rol idone (see Ren*? Amstutz, Bj6rn Ringdahl, Bo Karl^n, Margareth Rock and Donald J. Jenden, J. Med.

Chem. 1985, 28, 1760-1765) are introduced into a solution of 30.2 g (0.15 mol) of 6-cyano-3,4-d i hydro-2,2-d imethy -3 4-epoxy-2H-benzoCb3pyr an in 150 ml of dimethyl sulfoxide, and the mixture is stirred for 6 hours at 20°C. The reaction mixture is introduced into ice water, the precipitate is washed until neutral, dried and separated on a silica gel column using CH2CI2 CH3OH 19:1 and the product is rec r s t a 11 i zed from ethanol. The first compound obta ned is (-)-(3R, 4S, 5«R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2'-oxo-51 -methyl - 1'-pyrrolidinyl)-2H-benzoCb]pyran-3-ol.

Crystals of melting point: 184° ajj0 = -27.8° c = 1 n ethanol.

As the 2nd, slower-moving, product, (-)-(3S, 4R, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2'-oxo-5'-methyl-1-pyrol dinyl )-2H-benzoCb3pyran-3-ol is obtained after additional crystallizat on from ethanol.

Crystals of melting point: 258° ajj° = -86° (c = 1, ethanol) Example 3 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2'-oxo-3'-methyl-1 -pyrrol dinyl) -2H-benzoCb]pyran-3-ol Diastereomer A and diastereomer B Diastereomer B: 1.8 g (0.06 mol) of 80 % NaH are added to a solution of 16 g (0.056 mol) of 6-cyano-trans-3-bromo-3,4-dihydro- 2,2-d imethy l-2H-benzoCb]p r an-4-ol in 80 mL of dimethyl sulfoxide. After stirring for one hour at 20°, a further 2.4 g (0.08 mol) of 80 % N a H and 8.6 g (0.084 mol) of racemic 3-methyl-2-pyrrol idone are added, and the mixture is then stirred at 20° for 16 hours. After cooling and adding dropwise 160 ml of water, the precipitate is filtered off under suct on, washed with a little water and dried.

The crude product is r e c r y s t a 11 i z ed twice from ethyl acetate/methanol and subsequently from d i me t hy I f o r mam i de / methanol. The diastereomer can be isolated in pure form in this way .

Crystals of melting point: 261-263° NMR (do-DMS0) CH3 signals: δ 1.19 (3H, s) 1.21 (3H, s) 1.45 (3H, s) D.rasJfc reome A :·<· ■·■-.- ·····.' ·'■·'·· :··-· The mother liquors from the above experiment are evaporated, and the residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (9:1). Diastereomer A is separated off and rec rys ta 11 zed from ethanol.

Crystals of melting point: 210-211° NMR (d0-DMSO) CH3 signals: 1.13 (3H, d) 1.20 (3H, s) 1.47 (3H, s) Example 4 (3R*, 4S*, 5'S*)-3,4-dihydro-2,2-dimethyl-6-methylsulfonyl-4- (2* -OXO-5' -methyl-1 -pyrrol idinyl)-2H-benzoCb]pyran-3-ol 1.5 g (0.05 mol) of 80 % NaH are introduced into a solution of 10.2 g (0.04 mol) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-methylsul fonyl-2H-benzoCb]pyran and 4 g (0.04 mol) of racemic 5-me t hy L -2-py r ro L done in 50 m L of DMSO at 20°. The mixture is heated at 45°C for 30 minutes, stirred at 20° for 5 hours and poured into ice water.

The mixture is clarified using activated charcoal, and the product is salted out. The precipitate is filtered off under suction, and diastereomer A is separated off on a silica gel column using ethanol/ethyl acetate/toluene/ petroleum ether 2:2:1:1 and recrystal I ized from ethyl acetate .

Crystals of melting point: 190-193° NM Melting point: 64-65° (from a little petroleum ether) 2,2-D me t y I -6-me t hy Isu I f ony I c h romene is obtained by heating p-methylsul onylphenyl 1, 1-dimethylpropargyl ether in 1,2-dichlorobenzene at 180°.

Melting point: 107-108° (from diisopropyl ether) 3-Bromo-3,4-dihydro-2,2-dimethyl-6-meth lsulf ony 1-2 H-benzoCbDpy ran-4-ol is obtained from 2,2-dintethyl-6-methylsulf ony I chromene and N-bromosuc c i n i -mide in a 9:1 dimethyl sul o ide/H2n mixture.

Melting point: 140-141° from diisopropyl ether 3,4-D i hydro-2,2-dimethy l-3,4-epoxy-6-methy I sul f ony 1-2H-benzoCb]py r an is obtained by reacting 3-bromo-3,4-d i hydro-2,2-dimethyl-6-methylsulfonyl-2H-benzo[b]pyran-4-ol ith sodium hydride in DMSO.

Melting point: 165° (from ethyl acetate) Example 5 5 (3R*, 4S*, 5 ' S*)-2,2-dimethyl-7-methoxy-6-phenylsulf onyl- 4-(2'-oxo-5'-methyl-1 '-pyrrol idinyl )-2H-benzoCb]pyran- 3-ol and (3R*, 4S*, 5 · R* ) -2 , 2-d i me t h I -7-me t hoxy-6- phenylsulfonyl-4-(2'-oxo-5'-methyl-1'-pyrrolidinyl)-2H- benzoCb]pyran-3-ol 10 1.62 g (0.0675 mol) of NaH in the form of an 80 X strength suspension and 10.3 g (0.11 mol) of ( + ) -5-me t hy I -2-py r - rolidinone are added to a solution of 9.6 g of 3-bromo- 3/.4-dihydro-2/.2-dimethyl-7-methoxy-6-phenylsulfonyl-2H- 15 benzoCb]pyran-3-ol in 60 ml of dimethyl sulfoxide, and the mixture is stirred at 40° for 4 hours. The mixture is then poured into ice water and filtered under suction.

The residue is washed until neural, dried and subjected to chromatography on silica gel using the eluent toluene/ • .20 metJiy tjene ^trht or i de/im t-hanbl ~ tQ : 1:-1 ■ X-3 R * 4S* , 5 ' R* ) - 2.2-dimethyl-7-methoxy-6-phenylsulfonyl-4-(2'-oxo-5'- methyl-1 '-pyrrol idinyl )-2H-benzoCb]pyran-3-ol is eluted as the first major product: melting point: 214-15°C; NMR (d6-DMS0) i (ppm): 1.17; 1.27; 1.4 (s,s,s; 9H, 2 , 2-d i me t hy I 25 and 5-methyl).

The slower-moving (3R*, 4S*, 51 S* ) -2, 2-d i me t hy l-7-me t hoxy- 6-phenylsulfonyl-4-(2'-oxo-5'-methyl-1-pyrrolidinyl)-2H- benzoCb]py ran-3-ol is obtained as the second major product. 30 Melting point: 244 - 245°C; NMR (d0-DMSO) 6 (ppm): 0.73 (d, 3H, 5'-CH3) Preparation of the starting material: 35 3-Bromo-3,4-d hydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl- 2H-benzoCb]pyran-4-ol is obtained from 2,2-dimethyl-7- methoxy-6-phenylsul ony l-2H-chromene and N-bromosucc n - mide in a 9:1 mixture of dimethyl sulf oxide/H20.

Melting point: 202 - 203°C. 2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is obtained from 2 , -d i me t h l-4-hy d r o -7-me t hoxy-6-phen L -sulf ony L c h romane by means of pyr idine/phosphorus oxy-chloride in benzene.

Melting point: 140 - 141°C. 2 2-Di methyl -4-hydroxy-7-methoxy-6-phenylsu I fonylch romane is obtained from 2,2-d imethy l-7-methoxy-6-phenylsulf ony l-chroman-4-one by means of sodium borohydride in methanol. Melting point: 146 - 147°C. 2.2-Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is obtained from pheny I su I f ony I chloride, 2,2-d imeth I -7-methoxychroman-4-one and aluminum chloride in methylene chloride. Melting point: 223 - 225°C.

Example 6 (3R*, 4S*, 5'S*)-3,4-Dihydro-2,2-dimethyl-6-phenylsul-fonyl-4-[2' -oxo-5' -methyl-1-pyrrolidinyl-2H-benzoCb]pyran-3-0 l.:a.nd .3 R * 4S*> 5'vR *-3,4-dih yd ro-2 2-dim-e thyi-6-phenyl-sulfonyL-4-(2'-oxo-5'-methyL-1-pyrroLidinyl)-2H-benzo[b]-py ran-3-ol .

These compounds are prepared analogously to Example 5 using racemic 5-methy Ipyrrol idin-2-one. The mixture is subsequently separated on a silica gel column using methylene chloride/ethyl acetate/ethanol (94:3:3). (3R*, 4S*, 5'S*)-3,4-Dihydro-2,2-dimethyl-6-phenylsul- onyl-4- (2* -oxo-5 '-methyl-1 -pyrrol idinyl)-2H-benzoCb]pyran- 3-ol.

Crystals of melting point: 216-217° from ethanol NMR (d -DMSO) 5'-CH3 signal: θ.48 (3H, pseudo-doublet). (3R*, 4S*, 5'R*)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl- 4- (2'-oxo-5'-methyl-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol.

Crystals of melting point: 240-241°C from OMF/ethanol NMR (d6-DMSO> 5'-CH3 signaL: S 1.27 (3H, d) In addition to the compounds described in the examples, the compounds of the formula I shown in the table below can also be obtained according to the invention: I. (3R, 4S, 5'S)-3,4-dihydro-2,2-dimethyl-6-methyl- sulfonyl-4-[2'-oxo-5'-methyl-1-pyrrolidinyl)-2H- benzo[b]pyran-3-ol, 2. (3R*, 4S*, 5IS*)-6-cyano-3,4-dihydro-2,2-dimethyl-7- methoxy-4-C2' -oxo-5' -methyl-1-pyrrol idinyl ) -2H- benzo[b]pyran-3-ol, 3. (3R*, 4S*, 4'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-7- hydroxy-4-C2* -oxo-4' -methyl-1-pyrrol dinyl )-2H-benzoCb] pyran-3-ol, 4. (3R*„ 4S*, 3'R*)-3,4-dihydro-2,2-diethyl-6-nitro- 4[2' -oxo-3' -methyl-1-pyrrol idinyl )-2H-benzoCb]pyran- 3-ol, 5. (3R, 4S, 5 ' S ) -7-am i no-3,4-d i hydr o-2,2-d i me t hy I -6-n i t r 0-4- H-ben z.o C b Jpy r an -.3 -o L , 6. (3R*, 4S*, 5 'S*)-3,4-dihydro-2-methyl-2-ethyl-6- phenylsulfonyl-4-[2'-oxo-5'-methyl-1-pyrrolidinyl)- 2H-benzoCb]pyran-3-olr 7. (3R, 4S, 4»S)-3,4-dihydro-2,2-dimethyl-6-tolylsulfonyl- 4-C2' -oxo-4 '-propyl-1-pyrrol idinyl )-2H-benzoCb]pyran- 3-ol, 8. (3R*, 4S*, 3'S*)-3,4-dihydro-2,2-diethyl-6-Cp-nitroD- phenylsulf onyl-4-[2' -oxo-3' -methyl-1-pyrrolidinyl3-2H- benzoCb]pyran-3-ol, 9. (3R*, 4S*, 3»R*, 4,S*)-3,4-dihydro-2,2-dimethyl-6- Cp-cyano] -phenylsulfonyl-4-[2' -oxo-3 •-methyl-4' -methyl- 1 -pyrrol idinyl ]-2H-benzoCb]pyran~3-o I , 10. (3R*, 4S*, 5,S*)-3,4-dihydro-2^2-dimethyl-6-Cp-chloro]- phenylsulfonyl-4-C2'-oxo-5'-methyl-1-pyrrolidinyl]-2H- benzoCbJp r an-3-ol II. (3R, 4S, 3'R, 4'S)-3,4-dihydro-2-methyl-2-propyl)- 6Cp-methoxy]-phenyl sulfonyl-4-C2' -oxo-3* -methyl -4' - eth l-1-pyrrolidinyl]-2H-benzoCb]pyran-3-ol, 12. (3R*, 4S*, 4' R*)-3,4-dihydro-2,2-dimethyl-6-phenyl- sulfonyL-4-[2l-oxo-4'-meth l-1-pyrrolidin L3-2H-benzo Cb]py ran-3-oL , 13. (3R, 4S, 5 ■ S)-3 4-dihydro-2,2-diethyl-6-Cp-nitro]- phenyLsuLfonyL-4-C2'-oxo-5'-methyL-1-pyrroLidinyL]- 2H-benzoCb]p ran-3-oL , 14. (3R*, 4S*, 3,R*)-3,4-dihydro-2 ,2-dimethyl-6-Cp-cyano]- phenyLsuLfonyL-4-C2,-oxo-3'-methyl-1-pyrroLidinyL]- 2H-benzoCb]pyran-3-ol, 15. (3R*, 4S*, 5'S*)-3,4-dihydro-2if2-dimethyL-6-Cp-chLoro]- phenylsulfonyl-4-[2,-oxo-5,-ethyl-1-pyrrolidiny]-2H- benzoCb]p ran-3-oL , 16." (3R*, 4S*, 5'S*)-3,4-dihydro-2,2-dimethyl-6-phenyl- suLfonyL-4-C2'-oxo-5,-methyL-1-morphoLinyl]-2H-benzoCb] pyran-3-ol, 17. (3R*, 4S*, 6'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-4- [2'-oxo-6,-methyl-1-piperazinyl)~2H-benzo[b]pyran-3- ol, 18.' (3R*, 4S*, 2'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-- ·;·', Ι '-^Ό ο-2 -;methy L^3--t,h iazoteid inyl )^£HrrbenzoI-b3py ran- 3-ol, 19. (3R*, 4S*, 6' S*)-6-cyano-3,4-dihydro-2^2-diethyL-4- C2,-oxo-6,-meth l-1-piperidinyL)-2H-benzoCb]pyran-3-oL 20." (3R*, 4S*, 2'R -2,Z-diethyl-3,4-dihydro-6-Cp-chloro3- phenylsulfonyl-4-(5',-methyl-5*-oxo-3-oxazolinyl)-2H- benzoCb]pyran-3-ol.

Pharaacolog cal data The effect of the compounds on arterial, blood pressure was investigated on anesthetized normotensive maLe Sprague-Dawley rats. The anesthetic used was Nembutal in a dose of 70 mg/kg i.p. The blood pressure was measured using catheters in the Arteria carotis using a pressure transducer (Statham P 23 Db). For i.v. administration, the substances were dissolved in dimethyl sulfoxide and diluted with water. The concentration of the stock solution was 1 mg/ml, the solution containing 15 % of dimethyl sulfoxide. For injection, portions of * Not in ambit of the invention this stock solution were in each case freshly diluted with water .

Concentrations of 50 (100), 30 (30) and 10 (10) ug/ml were used for i.v. administration and 100 (100), 50 (60) and 30 (30) ug/ml for i.d. administration. The numbers given relate to experiment a), and the numbers in parentheses to experiment b).

The blood pressure was measured after 0, 0.2, 0.4, 1, 2, 3, 10, 15 and 30 minutes after i.v. administration and after 0, 1, 3, 5, 10, 15, 20, 30, 40, 50 and 60 minutes after i.d. administration. The ED25 values were determined from the minima of the respective blood-pressure curves . a) (+)-(3R*, 4S*, 5 ' S* ) -6-c y ano-3 , 4-d i hydro-2 , 2-d i me t hy l- 4-(2' -oxo-5' -methyl-1'-pyrrolidinyl)-2H-benzoCb]- pyran-3-ol ·■·■ -^ empOundi- yi.jro-m -. -E-Jca-ni te ."1.)·: ED25= 19 yg/kg (i.v.) ED25= 42 ug/kg (i.d.) b) (+)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2'-oxo- 1'-pyrrolidinyl-2H-benzoCb]pyran-3-ol (Example from J. Med. Chem. 1986, 29, 2194-2201) ED25= 42 ug/kg (i.v.) ED25= 82 g kg (i.d.) In vitro influence of Cl-induced rhythmic contractions on guinea-pig ureters Method: Male guinea pigs were sacrificed by a blow to the neck and hemorrhage from the carotid artery. Both ureters were removed immediately, excluding the region in the vicinity of the pelvis due to the pacemaker present therein. Each 2 cm segment was freed from connective tissue in a petri dish containing Tyrode solution and then suspended at a baseline tension of 4.9 mN ( = 0.5 p ) in a 25 ml organ bath (Messrs. Rhema Labortechnik, Hofheim). The organ bath contained a Tyrode solution kept at 37° and aerated with carbogen (95% of 02, and 5% of CO2 and having the following composition (mmol/l): NaCl 137, KCl 2.68, MgS04 1.05, CaCl2 1.8, NaH2P04 0.41, NaHC03 11.9, glucose 5.55.

The contractions were measured i somet r i c a 1 using Gould/ Statha UC2 transducers. After an equilibration period of at least 15 minutes, KCl was added to the organ bath _2 to give a concentration of 4 x 10 mol/l. The agonist was left in the bath for 2 minutes, during which time phasic contractions occurred without causing a significant increase in the baseline tone. On subsequent washing for 1 minute, the rhythmic contractions ceased immediately. After further addition of agonist and washing, the test substance (benzopyran derivative) was introduced into the organ bath (in the form of a solution in 0.1 ml of etha- nol, the final concentrations in all cases being 10~^ mol/l) and left. to act for one minute before adding agonist and washing. The following parameters were determined for each of the two-minute periods under the influence of KCl: 1. mean height of contractions, 2. frequency of contractions and 3. product of mean height and frequency of contractions.

The exclusion criteria were mean height contractions of below 4 mN or frequencies of less than 2/min in more than one of the four periods during which only the agonist KCl was present in the bath. The percentage inhibition by the test substance was evaluated in comparison to the mean value from the two preliminary runs.

In addition to the arithmetic mean (x), the standard error of the mean (SEM) was calculated.

Results : Compound mean height frequency, v k.v. n of contrac- Γ.%] C%] tions k [%] (-)-(3R,4S,5 ' R)-6- 75 + 8 89 + 4 96 + 2 7 cyano-3,4-dihydro- 2,2-dimethyl-4-(2'-oxo-5 ' -methyL-1 ' -pyrrol idinyl )-2H-benzoCb]pyran-3-ol from Example No. 2 +)-(3R*,4S*,5'R*)- 69 + 11 86 + 4 96 + 1 6 6-cyano-3,4-dihydro- 2,2-dimethyl-4-(2'-oxo-51 -methy 1-1 ' -pyrrol idinyl)-2H-benzoCb.lpyran-3-ol from Example No. 1 + ) τ-ό-cyan0-3, 4-d i - ·■■■■ 8 ;+ 8 , 58..+,, .5.. 61 + 7 7 hydro-2,2-dimethyl-trans-4-(2-oxo-1-pyr rol id inyl-2H-benzoCb]-pyran-3-ol (from J. Med. Chem. 1986, 29 2194-2201) n = number of ureters Reference: P. SCHIANTARELLI and w. URMANN .

Antispasmod c Activity of Rociverine on the Smooth Musculature of the Urinary Tract.

Arzneim.-Forsch./Drug Res. 30, 1102-1109 (1980)

Claims (19)

HOE 87/F 028 Patent c L a ims

1. An N-benzopy r any I Lactam of the formula I in which R1 represents CN, NO2, S0n- ( C <| -C0 ) -a I ky I or SOn-Ar; where n = 1 or 2, Ar represents an aro- as herein defined, matic or heteroaromatic system «h*ch iSxUnsubsti- tuted or substituted by 1 to 3 identical or different (C<|-C2>-alkyl, ( C 1 -C 2 ) a I k oxy , halogen, tr if luoromethyl, CN, O2, CO- ( C -J-CJ >-al ky I or - - SOp- ( C †- C >~a I k y I -r ad i.c a t s , . a nd p- fe es en ts 1 or 2, R2 represents H, OH, ( C 1 -C2 ) -a I koxy , C C -j-Cj ) - alkyl, halogen or NR5R6, where R5 and R6 are identical or different and represent H, (C-i-Cg - alkyl or ( C 1 - C 2 ) _al ky I c a r bony I , R^ and R^ are identical or different and represent alkyl having 1-4 carbon atoms, 1 2 the abovement i oned meanings of R and R may also be exchanged, and X represents a (CH2 m chain which is substituted by at least 1 and at most 2m-1 ( C 1-C > -a L ky I groups and may be—nterrupted by a heteroatom Y do- noting 0 NR^ or S, and ^ represents H or ■<-€-|—C )-alk l , and m represents 2, 3 or 4, where the configurations at C3 and C are always opposed.

2. A compound I as claimed in claim 1, wherein at Least one of the substituents or indices has the following meaning: R , R , R and are as defined in claim 1, X is a (CH2)m cha in which is substituted by a (C-j- C2)-alk l group and moy-bo intor rupto.d. by a — h o t o r o ■ < ■ ^^a-from ¥ which ι ¾μι minlj-O — r „„„..MD7 o? or C ) Jlh and where m represents 2, 3 or 4.

3. A compound I as claimed in claim 1 , wherein at least one of the substituents or indices has the following meaning: R^ to R^ are as defined in claim 1, X is a (CH2)m chain which is substituted by a (Ci-CgJ-alkyl group and where m represents 3 or 4.

4. A compound I as claimed in claim 1 , wherein at least one of the substituents or indices has the following meaning: RV to R^ a r e - as def irted i n c I a m .1 ·.. ,.. ....... X is a ( H2 m chain where m represents 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C-j-CjJ-alk l group.

5. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following mean i ng : 1 4 R -R are as defined in claim 1, X is a ( H2 ) m chain where m = 3 or 4 and which s substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (Ci-C2)-alkyl group, the conf guration of this carbon atom being the same as that of the C-4 atom of the chroman system.

6. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following meaning: ^-R are as defined in claim 1, X is a ( C H2 ) m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C<|-C2)_alkyl group, the configuration of this carbon atom being opposite to that of the C-4 atom of the chroman system.

7. A compound I as claimed in claim 1 , wherein at least one of the substituents or indices has the following meaning: 1 R denotes CN or SO2CH3, R2 denotes H, R3 and R4 are identical or different and denote ( C -j-Cg ) -a I ky I , and X denotes a (CH2 m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C1-C2)- alkyl group, the configuration of this carbon atom being the same as that of the C-4 atom in the chroman system.

8. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following meaning: 1 R denotes CN or SO2CH3, 2 R denotes H, R3 and R4 are identical or different and denote X denotes a (CH2)m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (C1-C2 - alkyl group, the conf guration of this carbon atom being opposite to that of the C-4 atom in the chroman system.

9. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following mean i ng : 1 R denotes SO^Ar where Ar equals phenyl which is unsubs t i tuted or substituted as defined in claim 1, 2 R denotes H or CH3, R^ and R^ are identical or different and denote ( C -j-Cg ) -a I ky I , and X denotes (CH2>m where m = 3 or 4, substituted on the carbon atom neighboring the nitrogen atom of the Lactam ring by a ( C -j - C 2 ) -a I ky L group, the conf iguration of this carbon atom being the same as that of the C-4 atom in the chroman system.

10. A compound as claimed in claim 1 , which is (-)-3R,- 4S, 5 · R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2 · -o o- 5 ' - methyl-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol.

11. A compound as claimed in claim 1, which is (-)-(3S,- 4 , 5'R)-6-cyano-3,4-dihydro-2 2-dimethyl-4-(2' -oxo-5'- methyl-1'-pyrrolidinyl)-2H-benzo[b]pyran-3-ol.

12. A process for the preparation of a compound I as claimed in claim 1, wherein in which R , R , R and R have the abovement mean ngs, is reacted with a lactam of the formula III compound of the formula in which R , R , R and R have the abovement i oned meanings, is reacted with a Lactam of the formula III, o r c) a compound of the formula V in which R , R , R and R have the abovement i oned meanings, is acylated to give a compound VI in which R to R and X are as defined above and Y denotes a leaving group, and the latter is cyclized give a compound I, or d) a compound of the formula VII in which R to R and X are as defined above, is oxidized to give a compound I. - 28 -

13. A pharmaceutical composition comprising a compound of the formula I as claimed in claim 1 for treating high blood pressure.

14. A pharmaceutical composition having an antihypertensive action, containing an effective amount of a compound I as claimed in claim 1.

15. A composition for treating high blood pressure, comprising an effective amount of a compound I as claimed in claim 1, together with pharmaceutically acceptable excipients.

16. A pharmaceutical composition for relaxing the urether, comprising a compound of the formula I as claimed in any of claims 6, 8 and 10.

17. A composition comprising a compound of the formula I as claimed in claim 1 for relaxation of the urether.

18. A medicament having a relaxed action, which contains an effective amount of a compound I as claimed in claim 1.

19. A composition for relaxing the urether, comprising an effective amount of a compound 1 as claimed in claim 1 together with pharmaceutically acceptable excipients. COHEN ZEDE «X RAPAPORT P. 0. Bo3? 33116 , Tel-Aviv