AU604089B2 - Alkyl-substituted n-benzopyranyllactams, a process for their preparation, their use, and pharmaceutical preparations based on these compounds - Google Patents

Description

6 4089 Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE

SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: Int. Class SComplete Specification Lodged: 4 0 0 Accepted: Published: Priority Related Art: This document contains the amendments rade under Section 49 and is cor;cct for printing.

Name of Applicant: Address of Applicant: Actual Inventor: Address for Service HOECHST AKTIENGESELLSCHAFT 45 Bruringstrasse, D-6230 Frankfurt/Main Federal Republic of Germany HEINRICH CHRISTIAN ENGLERT, HANS-JOCHEN LANG, DIETER MANIA, BERNWARD SCHOLKENS, ERIK KLAUS EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAMS, A PROCESS FOR THEIR PREPARATION, THEIR USE, ANDPHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS The following statement is a full description of this invention, including the best method of performing it known to us c i HOECHST AKTIENGESELLSCHAFT DR.vF/gm HOE 87/F 028 K Desc ript ion AlkyL-substituted N-benzopyranyLLactams, a process for their preparation, their use, and pharmaceuticaL preparations based on these compounds The invention relates to N-benzopyranyLLactams of the formuLa I 15 2 3 R

R

in which

R

1 represents CN, NO 2 SOn-(C1-C6)-aLkyL or\ SOn-Ar; where n =1 or 2, Ar represents 4 a 2 a a r .20m*: w hich'is unsubstituted or substituted by 1 to 3 identical or dlifferent (CC-C 2 )-aLkyL, (Cl-C 2 )aLkoxy, halogen, atrifLuoromethyL, CN, NO 2 CO-(Cl-C 2 )-aLkyL or sop-(C-C 2 )aLkyL radicals, and p represents 1 o r2,

R

2 represents H, OH, (Cl-C 2 )-aLkoxy, (Cl-C 2 alkyl, halogen or NRR where R and Rare identical or different and represent H, (Cl-C 2 aLkyL or (CC-C 2 )-aLkyLcarbonyl, R3and R4are identical or different and represent aLkyL having 1-4 carbon atoms, the abovementioned meanings of R 1 2n a ~ob exchanged, and X represents a (CH2)m c hain which is substituted by at Least 1 and at most 2m-1 (Cl-C 2 )-aLkyL groups and may be interrupted by a heteroatom Y dle- BI A L"Z noting 0, NR 7 or S, and R 7 represents H or (Cl-C 4 )-atkyL, and m represents 2, 3 or 4, where the configurations at C 3 and C 4 are always opposed.

-".-MOM

111;

I

-2 naphthyl or biphenylyl, and a 5- or 6-membered- eroaromatic system Ar is preferabLy a r of a 5- or 6membered N- and/or S-he ycLic ring, in particular furyl, thienyL hiazoLyL, oxazolyL, isoxazoLyL, Dyrazolyl i idazolyl, thiazoLyL, pyridyL, pyrazinyl, Halogen is taken to mean F, CL, Br or I, preferabLy F and CL.

44 4f 4 4 4 I 4 441411 4 4l t 4

(I

I 44 Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzo[blpyran system (caLLed "chroman system" beLow) of the formuLa I are asymmetrically substituted. The invention reLates 15 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 abovementioned definition of X means that, in addition, the Lactam ring 20 -cont-ains at L-east..one, bu-t-at -mos t 'm-(where ,m .has the definition mentioned initiaLLy) chiraL carbon atoms. In this case, the invention reLates both to compounds having R- and S-configured centers. The same applies in the 1 2 R R 3 R4 case where R 1

R

2 R or R contains centers of asymmetry 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

1

R

2 R and Rhave the abovementioned meanings and X represents a (CH2)m chain which is substituted by a (C 1

-C

2 )-alkyL group and may be interrupted by a 7 7 heteroatom Y which represents 0, S or NR where R denotes H or (C 2

-C

4 )-alkyl, and where m represents 2, 3 or 4.

Additionally preferred compounds of the formula I are those in which

R

1 to R 4 have the abovementioned meanings and X i 3 represents a (CH2)m chain which is substituted by a

(C

1

-C

2 )-alkyL group and where m represents 3 or 4.

Very particularLy preferred compounds I are those in which R1 to R have the abovementioned 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

1

-C

2 )alkyl group.

Especially preferred compounds are those in which R R have the abovementioned meanings and X represents a (CH2)m chain where m 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen 15 atom of the lactam ring by a (C 1

-C

2 )-aLkyL group, namely in a fashion such that the configuration of this carbon atom is the same as that of the C-4 atom of the chroman system.

e' 4 a 4 4 t* 20 -Likewise: very..part.ic'u.LarL..y.pr-eferr.ed-'c-ompounds I are 4 4, those in which R represents CN or S0 2

-CH

3 and R 2 represents H, R and R are identical or different and represent alkyl having 1 or 2 carbon atoms, X represents a (CH2)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 1

-C

2 )-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; especially preferred compounds I are those in which R represents S0 2 -Ar where Ar denotes phenyl which is unsubstituted or substituted as mentioned above by 1 to 3 substituents,

R

2 represents H or OCH 3

R

3 and R are identical or different and represent

(C

1

-C

2 )-alkyl, and X represents a (CH2)m chain where m 3 or 4 and which is substituted on the carbon atom neighboring 4 the nitrogen atom of the Lactam ring by a (C 1

-C

2 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.

Preferred compounds are also those in which R -R have the abovementioned meanings 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 1

-C

2 )-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.

o o Likewise very particularly preferred compounds I are S 15 those in which 1 2 R represents CN or S0 2

-CH

3 and R represents H,

R

3 and R are identical or different and represent alkyL having 1 or 2 carbon atoms, X represents a (CH2)m chain where m 3 or 4 and which is subs t'i-tut.ed -on the car.bo.n.a tomn neighboring the nitrogen atom in the lactam ring by a (C 1

-C

2 )-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; especially preferred compounds I are those in which SR represents S0 2 -Ar where Ar denotes phenyl which is unsubstituted or substituted as mentioned above by 1 to 3 substituents,

R

2 represents H or OCH 3

R

3 and R are identical or different and represent (Ci-C 2 )-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 1

-C

2 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 C 5 invention are described in J. Med. Chem. 1986, 29, 2194- 2201. They are summarized there under the following general formulae: zA

'V

4r V 4 44 4r I

(CH

2 _x

R

CP

3 where R R R Z, n, m and R have the meanings specified therein. The majority of these compounds is also described in various patent applications, of which the following may be mentioned: EP 107,423, EP 120,427, EP 076,075 and EP 120,428.

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-reducing properties and which differs from the known compounds above all by the fact that they carry additional substituents, as defined above, in the lactam ring as a substituent on C-4 of the chroman system.

Compared to the previously known unsubstituted compound, S- 6 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 Longterm therapy, such as the treatment of hypertonia, where it is in some cases necessary for a medicament to be taken for life.

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 transposition to one another for an optimum antihypertensive action. In contrast, a cis-arrangement leads to a significant weakening of the effect. Such trans-configures compounds also occur in the form of antipodes. It was possible to show, with reference to an example, that the (->-antip.ode -has -a far--stronger .action t-han the antipode. The (-)-antipode was in this case assigned the 4R, 3S-configuration (cf. EP 0,120,428).

By introducing substituents into the lactam ring in accordance 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 differentiated 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 opposed with respect to the configuration 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 diastereoisomeric .f 7 compounds of the formula I. Surprisingly, the abovementioned advantageous properties of the compounds I can in many cases only be observed for one of the two diastereoisomers, while the other is substantiaLLy Less active than the corresponding unsubstituted compound. These are preferably compounds I which carry an aLkyl substitutent on the lactam carbon atom neighboring the Lactam nitrogen and whose relative configuration is identical to that of the C-4 atom in the chroman system.

The introduction of substitutents into 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 substituen.ts in the benzo part, .where aryl h;as the meaning ,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 i 8 Br

R

in which R R R and R have the abovementioned meanings, are reacted with Lactams of the formuLa III b) compounds of the formula IV RI IV, gR R3 R 4

R

3 and R have the abovementioned lactams of the formuLa III, 1 2 in which R R 2 meanings, are. reacted with or 4 ,I 4 9 t 20 c) compounds of the formula V

NH

no2 3 R1 OH R2 3 in which R, R R 3 and R have the abovementioned meanings, are acyLated to give the compounds VI

RN

4

R

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 I_ i

I

9 d) compounds of the formula VII Nj 2 R2 VII,

R

in which R to R and X are defined as above, are oxidized to give the compounds I.

I, If the compounds I are prepared by methods a) or this preparation takes place by reacting the compounds IV or II with the Lactams III in a suitable soLvent, preferably in dipolar aprotic solvents, such as dimethyl sulfoxide or THF, preferably with the involvement of bases, such as sodium hydride, potassium tert-butylate or similar bases which are known to be suitable for Lactam N-alkylations.

The reaction temperature in this reaction can be varied .within a broad-range, and the reaction is preferably carried out between 00C and room temperature. When racemic or optically uniform lactams III are used, at Least two new products of the formula I are obtained. These pro- H ducts can be separated by conventional methods, such as 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 spectroscopy. Optically uniform, i.e. enantiomerically pure compounds I can be obtained by subsequent racemate resolution. However, if lactams III which are already enantiomerically pure are used, the diastereoisomeric compounds I are likewise obtained in enantiomerically pure 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 ;li I- i 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 abovementioned meanings. They can be prepared, for example, according to the following equation: 2,3-dihydro-2H-benzoEblpyran-4-ones of the formula VIII 0 4R3

VIII

are reacted with acid chlorides Ar-S0 2 -CL in a fashion which is known per se in the manner of the Friedel-Crafts acylation, to give compounds of the formula IX SO IX, 3 S 20

R

in which R represents ArSOn (where Ar and n are as defined above) and in which R R and R are as defined above. These compounds IX are converted through reductions under standard conditions, such as by means of NaBH 4 in methanol, into compounds X 08 I I x

R

and the latter are subsequently subjected to elimination of water, for example by means of pyridine/phosphorus oxychloride, giving 2H-benzo[b3pyrenes of the formula XI:

XI.

2 3 Compounds XI can easily be converted by standard methods into the epoxides IV or the bromohydrins II. If, in this

I

L_ 11 2 reaction sequence, R denotes NH 2 or OH, protecting groups, such as, for exampLe, the dimethylaminomethyLene group for NH 2 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 antihypertensives 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 intravenously), in the form of capsules, coated tabLets, tablets, powders, suppositories or soLutions with additives or without additives of gatenic 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 -of abou-t 75 kg. They.- re. suita.bt-e f.or treatment of hypertonia, 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.

ExampLe 1 4S*, 5'S*)-6-cyano-3,4-dihydro-2,2-dimethy-4-E2'oxo-5'-methyl-1-pyrrolidinyL)-2H-benzoEb3pyran-3-o and 4S*, 5'R*)-6-cyano-3,4-dihydro-2,2-dimethyL-4-E2'oxo-5'-methyl-1-pyrrolidiny)-2H-benzoEblpyran-3-oL.

3.6 g (0.12 mol) of 80 NaH (suspension in oil) are introduced into a solution of 32 g (0.113 mol) of 6-cyanotrans-3-bromo-3,4-dihydro-2,2-dimethyL-2H-benzoEblpyran- 4-ot in 200 mL of DMSO at 200. 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-pyrrotidone are introduced. After stirring overnight at 200 the reaction 4 mixture is poured into ice water, and the precipitate is recrystalLized from methanol.

II The recrystallized mixture is separated on a silica gel 5 column using CH 2

CI

2

/CH

3 OH 4S*, 6-cyano-3,4-dihydro-2,2-dimethyL--4-[2'-oxo-5'-methyLl'pyrroLidinyL]-2H-benzo~blpyran-3-oL is isolated and recrystallized repeatedly from ethanol.

ii0 crystals of melting point: 239-240O NMR (d 6 -DMSO) CH 3 signals 6' 0.80 (3H, dl) 1.17 (3H, s) 1.45 (3H, s) AnaLysis: acatdfr307 calclate forC 17

H

20

N

2 -0 3 :303 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 4S*, Ii 2 ~.-6-cy-no-3,-di yr72-2--dimethyL--4-L2'--oxo-5'-methyL-1'pyrroLidinyL)-2H-benzolbjpyran-3-oL is concentrated, is evaporated, and the compound is isolated on a silica I gel column using CH 2

CI

2

/CH

3 OH (95:5).

Crystals of melting point: 190-1920 (from ethyl acetate) I NMR Cd 6 -DMSO) CH 3 signals 4 1.20 (3H, s) 1.30 (1.5H, s) 1' 1.43 (4.5H, s) V Analysis: crLcuLated for C 17

H

20

N

2 0 3 300.37 caic. C, 67.98; H, 6.71; N, 9.33 found C, 68.0; H, 6.7; N, 9.4 ExampLe 2 4R, 5' R)-6-cyano-3,4-dihydro-2,2-dimethyL-4-E21 oxo-5'-methyL-1-pyrroL idinyL )-2H-benzolblpyran-3-oL and 4S, 5' R)-6-cyano-3,4-dihydro-2,2-dimethyL-4-[2' 13 oxo-5'-methyL-1-pyrroL idinyl)-2H-benzolblpyran-3-oL 6 g (0.2 mol) of 80 NaH and 15 g (0.15 mol) of methyL-2-pyrrolidone (see Ren'e Amstutz, Bj8rn Ringdahl, Bo KarL~n, Margareth Rock and Donald J. Jendlen, J. Med.

Chem. 1985, 28, 1760-1765) are introduced into a solution of 30.2 g (0.15 moL) of 6-cyano-3,4-dihydro-2,2-dimethyL- 4 3,4-epoxy-2H-benzollpyran in 150 mL of dlimethyL suLfoxidle, and the mixture is stirred for 6 hours at 20 0 C. The reaction mixture is introduced into ice water, the precipitate is washed untiL neutral, dried and separated on a silica gel column using CH 2

CI

2

/CH

3 OH 19:1 and the pro- I duct is recrystallized from ethanol. The first compound 4 obtained is 4S, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyL-4-(2'- {j oxo-5'-methyL-1'-pyrroLidinyL)-2H-benzolblpyran-3-oL.

iiCrystals of melting point: 184 0 a 20 .27.80 c =1 in ethanol.

As the 2nd, sLower-moving,product, 4R, 4 6-cyano-3,4-dihydro-2,2-dimethyL-4-(2 '-oxo-5 '-methyL-ipyroLidinyL)-2H-benzo~blpyran-3-oL is obtained after addlitionaL crystallization from ethanol.

Crystals of melting point: 2580 a 20 _860 (c1l, ethanol)

D

ExampLe 3 6-Cyano-3,4-dihydro-2,2-dimethyL-trans-4-(2' -oxo-3 '-methyl- 1-pyrroLidinyL)-2H-benzo~blpyran-3-oL Diastereomer A and dliastereomer B Diastereomer 8: 1.8 g (0.06 mat) of 80 NaH are added to a soLution of 16 g (0.056 mot) of 6-cyano-trans-3-bromo-3,4-dihydroi 14 2,2-dimethyl-2H-benzo~blpyran-4-ol in 80 mL of dimethyL sulfoxide. After stirring for one hour at 200 a fur ther 2.4 g (0.08 moL) of 80 NaH and 8.6 g (0.084 mol) of racemic 3-methyL-2-pyrrolidone are added, and the mixture is then stirred at 200 for 16 hours. After cooling and adding dropwise 160 mi of water, the precipitate is filtered off under suction, washed with a little water and dried.

The crude product is recrystallized twice from ethyl acetate/methano and subsequently from dimethyLformamide/ methanoL. The diastereomer can be isolated in pure form in this way.

Crystals of melting point: 261-2630 NMR (d 6 -DMSO) CH 3 signals: 6 1.19 (3H, s) 1.21 (3H, s) 1.45 (3H, s) 1 20 Dias.ter-eomer A: Is The mother liquors from the above experiment are evaporated, and the residue is chromatographed on a silica geL column using ethyl acetate/petroleum ether Diastereomer A is separated off and recrystaltized from ethanoL.

Crystals of melting point: 210-2110 NMR (d 6 -DMSO) CH 3 signals: J 1.13 (3H, d) 1.20 (3H, s) 1.47 (3H, s) Exampe 4 4S*, 5'S*)-3,4-dihydro-2,2-dimethy-6-methysuLfonyL- 4-(2'-oxo-5'-methyl-1-pyrrolidinyl)-2H-benzoEblpyran-3-oL g (0.05 mol) of 80 NaH are introduced into a solution of 10.2 g (0.04 mot) of 3,4-dihydro-2,2-dimethy-3,4epoxy-6-methylsufony-2H-benzoEb3pyran and 4 g (0.04 moL) i of racemic 5-methyL-2-pyrroLidone in 50 mL of DMSO at 200. The mixture is heated at 45 0 C for 30 minutes, stirred at 200 for 5 hours and poured into ice water.

The mixture is ciarified using activated charcoaL, and the product is saLted out. The precipitate is fiLtered off under suction, and dliastereomer A is separated off on a siLica gel column using ethanol/ethyL acetate/toLuene! petroLeum ether 2:2:1:1 and recrystaLLized from ethyl acetate.

4 CrystaLsof meLting point: 190-1930 NMR Cd 6 -DMSO) CH 3 signaLs: &0.74 (3H, d) 1.18 (3H, s) 1 .47 (3H, s) Preparation of the starting material: p-MethyLsuLfonyLphenyL 1, 1-dimethyLpropargyL ether is obtained from p-methyLsuLfonyLphenoL and 3-methyL-3- 0 .c.hLo rbu t~yne i n a-mann e-r wh ic h is k nown pe r s e Melting point: 64-650 (from a Little petroLeum ether) 2,2-DimethyL-6-methyLsuLfonyLchromene is obtained by heating p-methyLsuLfonyLphenyL 1,1-dimethyLpropargyL ether in 1,2-dichLorobenzene at 1800.

Melting point: 107-1080 (from diisopropyL ether) V 30 3-Bromo-3,4-di hydro-2,2-dimethyL-6-methyLsuLfonyL''2Hbenzo~blpyran-4-oL is obtained from 2,2-dimethyL-6-methyLsuLfonyLchromene and N-bromosuccinimide in a 9:1 dimethyL suLfoxide/H 2 0 mixture.

MeLting point: 140-1410 from diisopropyL ether 3,4-Dihydro-2,2-dimethyL-3,4-epoxy-6-methyLsuLfoflyL-2H benzoEblpyran is obtained by reacting 3-bromo-3,4-dihydro- 2,2-dimethyL-6-methyLsuLfonyL-2H-benzo~blpyran-4-oL with sodium hydride in DMSO.

-16- IjMeLting point: 1650 (from ethyL acetate) ExampLe C3R*, 4S*, 5'S*)-2,2-dimethyL-7-methoxy-6-phenyLsuLfonyL- 4-C2'-oxo-5'-methyL-1 '-pyrroLidinyL)--2H-benzo~blpyran- 3-oL and 4S*, 5'R*)-2,2-dimethyL-7-methoxy-6phenyLsuLfonyL-4-C2'-oxo-5'-methyL-l'-pyrroLidinyL)-2Hbenzo~blpyran-3-oL 1.62 g (0.0675 moL) of NaH in the form of an 80 strength suspension and 10.3 g (0.11 moL) of C+)-5-methyL-2-pyr- '1 roLidinone are added to a solution of 9.6 g of 3-bromo- 3,4-di hydro-2,2-dimethyL-7'-methoxy-6-phenyL suLfonyL-2Hbenzo~bjpyran-3-oL in 60 mL of dlimethyL suLfoxidle, and the mixture is stirred at 400 for 4 hours. The mixture II is then poured into ;ce water and fiLtered under suction.

The residue is washed until neural, dried and subjected to chromatography on silica gel using the eLuent toLuene! Xmet-.yL.ene 'chlor ide/-met-hanoL' 10: 1 Q3R*, 4S*, Li 2,2-dimethyL-7-methoxy-6-phenyLsuLfonyL-4-(2 methyl-i '-pyrroL idinyL )-2H-benzolblpyran-3-oL is eLuted as the first major product: melting point: 214-15 0 C; NMR (d 6 -DMSO) S (ppm): 1.17; 1.27; 1.4 Cs,s,s; 9H. 2,2-dimethyL and The slower-moving 4S*, 5'S*)-2,2-dimethyL-7-methoxy- 6-phenyLsuLfonyL-4-(2'-oxo-5'-methyL-1-pyrroLidinyL )-2H- MeLting point: 244 2450 C; NMR (d 6 -DMSO) S (ppm): Preparation of the starting material: 3-Bromo-3,4-di hydro-2,2-dimethyL-7-methoxy-6-phenyLsuLfonyL- 2H-benzo~blpyran-4-oL is obtained from 2,2-dimethyL-7methoxy-6-phenyLsuLfonyL-2H-chromene and N-broniosuccinimide in a 9:1 mixture of dimethyL suLfoxide/H 2 0, Melting point: 202 203 0

C.

-17 2,2-D imethyL-7-methoxy--6-phenyLsuLfonyL-2H-chromene is obtained from 2,2-dimethyL-4-hyd roxy-7-methoxy-6--phenyLsulfonyLchromane by means of pyridline/phosphorus oxychLoride in benzene.

MeLting point: 140 141 0

C.

2,2 -D imethyL-4-hydroxy--7-methoxy-6-phenyLsuLfonyLchromane is obtained from 2,2-dimethyL-7--methoxy-6-phenyLsuLfonyLchrompn-4-one by means of sodium borohydridle in methanoL.

Melting point: 146 147 0

C.

2,2-D imethyL-7-methoxy-6--phenyLsuLfonyL chroman-4-one is obtained from phenyLsuLfonyL chLoridle, 2,2-dimethyL-7methoxychroman-4-one and aLuminum chLoride in methyLene chloridle. MeLting point: 223 225 0

C.

Example 6 (3R* 4S* 51 -D hdo2 2-ie h L6pey s L fonyL-4-[21-oxo -5'1-methyL-1-pyrroLidinyL-2H-benzo[blpyran- 20.3--oL :and 3R~ 4S* 5 1R 73,4-d ihy-dro-2,2-d4kmethyL-6-phenyL suLfonyL-4-C2'-oxo-5 '-methyL-1-pyrroL idinyL )-2H-benzo[b]pyran-3-oL.

These compounds are prepared analogously to ExampLe 5 using racemic 5-methyLpyrroLidin-2-one. The mixture is subsequentLy separated on a silica gel coLumn using methyLene chloride/ethyl acetate/ethanol (94:3:3).

(3R ,4S ,51S )-3,4-Dihydro-2,2-dimethyl-6-phenyLsuLfonyl-4-(2'-oxo-5 '-methyL-1-pyrroL idinyL )-2H-benzo[blpyran- U 3-al.

Crystals of melting point: 216-2170 from ethanol NMR (d 6 -DMSO) 5'-CH 3 signal: S 0.48 (3H, pseudo-doublet).

(3R* 4S* 51R 3 ,4-Dihydro-2,2-dimethyL-6-pheny~su~fonyL- 4 26 -oxo-5'-methyL-1-pyrroLidinyL)-2H-benzo~blpyran-3-oL.

Crystals of melting point: 240-241 0 C from DMF/ethanol 18 NMR (d 6 -DMSO) 5'-CH 3 signaL: S 'j.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: 1. (3R, 4S, 5'S)-3,4dihydro-2,2-dimethyL-6methyL- SuiLfonyL-42-ooO5'fethyL1-pyrroL idinyL)-2Hbenzo~bjpyrafl 3 -oL, 2. C3R*k 4S*, 5'S*)-6cyano-3,4-dihydro-2,2dimfethyL-7 Imethoxy4E[21oxo-5fethyL1-pyrroLidinyL)- 2

H-

benzo~blpyrafl 3 -oL, 3. 4S*, 4'S*)-6-cyano-3,4-d-'hydro-2,2-dimethyL-7 hydroxy4[2oxo-49-methyL1-pyrro~idinyL )-2H-benzo~bI pyran- 3 -oL, 4. 4S*, 3'R*)-3,4dihydro2,2diethyL-6nitro- 4E2'-oxo-3'-methyL-1-pyrroL idinyL )-2H-benzoEbjpyran- 3-oL, O3R, 4S, 5' S)-7-amino3,4dihydro-2,2dimethyL6nitro- 4 6. C3R*, 4S*, 5'S*)-3,4dihydro-2methyL2ethyL- 6 phenyLsuLfonyL4[2'0xo- 5 -methyL-1-pyrroLidilYl)- 2H-benzo~blpyran3-oL, I'7. O3R, 4S, 4'S)-3,4-dihydro-2,2-dimethyL-6toLyLsuLfonyL- 4-E2'-oxo-4'-propyL-1-pyrroL idinyL )-2H-benzolbjpyran- 8. C3R*, 4S*, 3' S*)-3,4-dihydro-2,2-diethyL6EpnitroJphenyLsuLfonyL- 4

E[

2 -oxo-3'-methyL-1pyrroL idinyL]-2H- V benzolblpyran-" 3

-L,

9. 4S*, 4'S*)-3,4-dihydro-2,2-dimethyL- 6 [p-cyano)-phenyLuLfonyL- 4 2 -oxo-3'-methyL-4'methYL- 1-pyrroL idinyL]-2H-benzobJpyran 3 -oL, 4S*, 5'S* -iy r -im ty -p c~ r l phenyLsuLfonyL-42Ioxo-5methyL1-pyrroLidinyL] 2

H-

benzo~bjpyran3-o, 11. O3R, 4S, 3'R, 4'S)-3,4-dihydro-2-methyL-2PropyL)- 6Ep-methoxy>-phenyLsuLfoflyL4-E 2 '-oxo-3 -methyl-4 ethyL-1-pyrroLidinyL)2H-benlOb)pyrn3oL, Ohl -19- 12. C3R*, 4S*, 4'R*)-3,4-dihydro-2,2-dimethyL-6-phenyLsuLfonyL-4-E2'-oxo-4'-methyL-1-pyrroLidinyL]-2H-belzo [bjpyran-3-oL, 13. (3R, 4S, 5 'S)-3,4-dihydro--2,2-diethyL-6--Ep-nitro]phenyLsuLfonyL-4-E2'-oxo-5 '-methyL-1-pyrroL idinyL]- 2H-benzo[blpyran-3-oL, 14. 4S*, 3' R*)-3,4-dihydro-2,2-dimethyL-6-Ep-cyanolphenyLsuLfonyL-4--E2'-oxo-3'--methyL-1-pyrroLidiflyL]- 2H-benzo~blpyran-3-oL, 15. 4S*, 5'S*)-3,4-dihydro-2,2-dimethyL-6-Ep-chLoroJphenyLsuLfonyL-4-E2 '-oxo-5 '-ethyL-1-pyrroL idinyJ-2Hbenzo~blpyran-3-oL, 16. C3R*, 4S*, 5'S*)-'3,4-dihydro-2,2-dimethyL--6-phenyLsuLfonyL-4-E2'-oxo-5 '-methyL-1-morphoi inyL]-2H-benzo~bI pyran-3-oL, 17. C3R*, 4S*, 6'S*)-6-cyano-3,4-dihydro-2,2-dimethyL-4- E2'-oxo-6'-methyL-1-piperazinyL)-2H-benzolblpyran-3o L, 18. 4S*, 2'S*)-6-cyano-3,4-dihydro-2,2-dimethyL-4- 2. 20 .E4'-0xoyo-,2-'-methyL-3-thiazoLidinyL)-2H-benzolblpyran- 1419. 4S*, 6' S*)-6-cyano-3,4-dihydro-2,2-diethyL-4- [2'-oxo-6'-methyt-1-piperidinyL )-2H-benzoEb~pyran-3-oL, 4S*, 2' R*)-2,2-diethyL-3,4-d ihydro-6-Ep-chLoroJphenyLsuLfonyL-4-(5 ',-methyL-5 '-oxo-3-oxazoL inyL )-2Hit benzo~blpyran-3-oL.

PharmacoLogical data The effect of the compounds on arteriaL blood pressure was investigated on anesthetized normotensive male I R j Sprague-Dawley rats. The anesthetic used was NembutaLR 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 dlissolved in dlimethyL suLfoxidle and diluted with water. The concentration of the stock solution was 1 mg/mI, the solution containing of dlimethyL suLfoxidle. For injection, portions of i i i 1 20 this stock solution were in each case freshly diluted with water.

Concentrations of 50 (100), 30 (30) and 10 (10) pg/ml were used for i.v. administration and 100 (100), and 30 (30) pg/ml for i.d. administration. The numbers given relate to experiment 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 ED 2 5 values were S°o "determined from the minima of the respective blood-pressure o o 15 curves.

o o94 a) 4S*, 5'S*)-6-cyano-3,4-dihydro-2,2-dimethyl- 4-(2'-oxo-5'-methyl-1'-pyrroLidinyL)-2H-benzo[b]pyran-3-ol .20 .(Compound from Example 1):

ED

2 5 19 ug/kg ED 2 5 42 pg/kg b) (+)-6-cyano-3,4-dihydro-2,2-dimethyL-trans-4-(2'-oxo- 1'-pyrrolidinyl-2H-benzo[blpyran-3-oL (Example from J. Med. Chem. 1986, 29, 2194-2201)

ED

2 5 42 pg/kg ED 2 5 82 pg/kg In vitro influence of KCL-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, 21 Hofheim). The organ bath contained a Tyrode solution kept at 370 and aerated with carbogen (95% of 02, and of CO 2 and having the foLLowing composition (mmoL/L): NaCL 137, KCL 2.68, MgSO 4 1.05, CaCL 2 1.8, NaH 2

PO

4 0.41, NaHCO 3 11.9, glucose 5.55.

The contractions were measured isometricaLLy using GouLd/ Statham UC2 transducers. After an equilibration period of at Least 15 minutes, KCL was added to the organ bath 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 ethanoL, the finaL concentrations in aLL cases being mol/l) and Left.to act for one minute before adding KCL Subsequent. washing was fo.LLowe.d by twice 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 Sthe test substance was evaluated in comparison to the mean value from the two preliminary runs.

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

22 Results: Compound mean height of contractions k 1%] frequency, I %I v k .v.

IE%I

75 8 89 4 96 2 7 cyano-3,4-dihydroo2-d I me thy L--2pyrroL idinyL )-2Hbenzolblpyran-3-oL from Example No. 2 69 11 86 4 96 1 6 6-cyano-3,4-dlihydro- 2,2-dlime thy 1-4-CE'oxo-51-methyL-1 pyrroL idinyL )-2Hb( nzolblpyran-3-oL from Example No. 1 +)-6-cyano-3,4-dihydro-2,2-dimethyLtrans-4-(2-oxo-lpyrroL idinyl-2Hbenzolb]-pyran-3-OL (from J. Med. Chem.

1986, 29 2194-2201) 8 .8 58 5 61 7 n number of ureters Reference: P. SCHIANTARELLI and w. MURMANN.

Antispasmodic Activity of Rociverine on the Smooth Muscu- Lature of the Urinary Tract.

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

Claims (10)

1. An N-benzopyranyltactam of the formula I 6o 01 R 1 6 I, 2 1 4 in which 11 Rl represents CN, NO 2 SOn-(C 1 -C6)-aLkyL or SO,-Ar; where n 1 or 2, Ar represents atie 8htri- O:wt cL which is unsubsti- tuted or substituted by 1 to 3 identicaL or dif- ferent (C 1 -C 2 )-aLkyL, (C 1 -C 2 )aLkoxy, halogen, trifluoromethyL, CN, N02, CO-(C 1 -C 2 )-aLkyL or sop-(C 1 -C 2 -aLkyL radicaLs, and p represents 1 or 2, 2 R represents H, OH, (C 1 -C 2 )-aLkoxy, (CC-C 2 5 6 5 6 alkyl, halogen or NR R ,where R and R are identical or different and represent H, (C 1 -C 2 alkyl or (C 1 -C 2 )-aLkyLcarbonyL, 3 4 R and R are identical or different and represent alkyL having 1-4 carbon atoms, 1 an the abovementioned 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 2 )-alky groups and may be interrupted by a heteroatom Y de- noting 0, NR 7 or S, and R 7 represents H or (C 1 -C 4 )-akyL, and m represents 2, 3 or 4, where the configurations at C 3 and C 4 are always opposed. 24

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 R are as defined in claim 1, X is a (CH2)m chain which is substituted by a (C 1 C 2 )-alkyl group and may be interrupted by a hetero- atom Y which represents 0, S or NR where R denotes H or (C 2 -C 4 )-aLkyL, 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: 1 4 R to R are as defined in cLaim 1, X is a (CH2)m chain which is substituted by a (C 1 -C 2 )-aLkyL group and where m represents 3 or 4. V 4. A compound I as claimed in cLaim 1, wherein at Least one of the substituents or indices has the foLLowing meaning: SR to R are-.as defined in claim 1, X is 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 1 -C 2 )-alkyL group. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the foLLowing meaning: 1 4 R -R 4 are as defined in claim 1, X is 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 1 -C 2 )-alkyL group, the configuration 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: 1 4 as defined in caim R -R are as defined in claim 1, 25 X is a (CH 2 )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 1 -C 2 )-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: R denotes CN or SO2CH 3 R denotes H, R 3 and R are identical or different and denote (C 1 -C 2 )-alkyl, 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 (C 1 -C 2 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: R denotes CN or S0 2 CH 3 R 2 denotes H, R 3 and R are identical or different and denote (C 1 -C 2 )-alkyl, 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 (C 1 -C 2 alkyL group, the configuration 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 meaning: R denotes S0 2 Ar where Ar equals phenyl which is unsubstituted or substituted as defined in claim 1, Li -26- R denotes H or CH 3 R and R are identical or different and denote (CC-C 2 )-aLkyt, and Ix denotes (CH2)m where m =3 or 4, substituted on the carbon atom neighboring the nitrogen atom of the Lactam ring by a (Cl-C 2 )-aLkyL group, the con- figuration of this carbon atom being the same as that of the C-4 atom in the chroman system. A compound as claimed in claim 1, which is 4S, 5 'R)-6-cyano-3,4-dihydro-2,2-dimethyL-4-(21 methyl-1l-pyrroLidinyL)-2H-benzo~blpyran-3-oL.

11. A compound as cLaimed in cLaim 1, which is 4R, 5'R)-6-cyano-3,4-dihydro-2,2--dimethyL-4-(2'-oxo-5 methyl-i '-pyrroL idinyL )-2H-benzoEb~pyran-3-oL.

12. A process for the preparation of a compound I as claimed in claim 1, wherein -a -c-ompoeund of t-h e f o-r m u La-iilU RBr I 3 R4 R in which R, R, R 3 and Rhave the aoee-ue m ea n in gs 6 ec is reacted with a Lactam of the formula III o r b) a compound of the formula IV

27- in which R R 2 R and R have the t--ee e meanings deS ea is reacted with a Lactam of the formula III, or c) a compound of the formuLa V R 2 in which R, R R and R have the eme, .ed i meanings )W C is acyLated to give a compound VI R l VI I R2O A VI in which R to R and X are as defined above and Y denotes a leaving group, and the Latter is cycLized to give a compound I, or d) a compound of the formula VII 1 .2 R2- 4 in which R 1 to R and X are as defined above, is oxidized to give a compound I. -28- V 13. A method of treatment of high blood pressure comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound of the formula I as claimed in claim 1. 14. A pharmaceutical composition for use in relaxation of the ureter and in the treatment of high blood pressure comprising a pharmaceutically effective amount of a compound of the formula I as claimed in claim 1 in adjunct with pharmaceutically acceptable carriers and excipients. 15. A method of treating high blood pressure wherein an effective amount of a pharmaceutical composition as claimed in claim 14 is administered to a patient suffering therefrom. 16. A method of antihypertensive treatment comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound of the .444. formula I as claimed in claim 1. 17. A method of relaxation of the ureter comprising o° administering to a patient requiring such treatment a pharmaceutically effective amount of a compound of the formula I as claimed in any one of claims 1, 6, 8 and 18. A method of relaxing the ureter, wherein an effective amount of a pharmaceutical composition as claimed in claim 14 is administered to a patient requiring such treatment. DATED this 14th day of August, 1990. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT ATTORNEYS 2ND FLOOR "THE ATRIUM", 290 BURWOOD ROAD, HAWTHORN, VIC. 3122. AUSTRALIA Melb Disk 7/1.30 MG _z