IE60932B1 - Alkyl-substituted N-benzopyranyllactams, a process for their preparation, their use, and pharmaceutical preparations based on these compounds - Google Patents

Alkyl-substituted N-benzopyranyllactams, a process for their preparation, their use, and pharmaceutical preparations based on these compounds

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Publication number
IE60932B1
IE60932B1 IE29588A IE29588A IE60932B1 IE 60932 B1 IE60932 B1 IE 60932B1 IE 29588 A IE29588 A IE 29588A IE 29588 A IE29588 A IE 29588A IE 60932 B1 IE60932 B1 IE 60932B1
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compound
alkyl
substituted
formula
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IE29588A
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IE880295L (en
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Erik Klaus
Dieter Mania
Bernward Schoelkens
Heinrich Englert
Hans-Jochen Lang
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Hoechst Ag
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Priority claimed from DE19873703229 external-priority patent/DE3703229A1/en
Priority claimed from DE19873724876 external-priority patent/DE3724876A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE880295L publication Critical patent/IE880295L/en
Publication of IE60932B1 publication Critical patent/IE60932B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

N-Benzopyranyllactams of the formula I in which R' represents CN, NO2 or SOn-Ar; where n = 1 or 2, Ar represents an aromatic or heteroaromatic system which is unsubstituted or substituted and p represents 1 or 2, R<2> represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl, halogen or NR<5>R<6>, where R<5> and R<6> are identical or different and represent H, (C1-C2)-alkyl or (C1-C2)-alkylcarbonyl, R<3> and R<4> are identical or different and represent alkyl having 1-4 C atoms, the abovementioned meanings of R<1> and R<2> can also be exchanged, X represents a chain (CH2)m, which is substituted by at least 1 and at most 2m-1 (C1-C2)-alkyl groups, and can also be interrupted by a heteroatom Y having the meaning O, NR<7> or S and R<7> denotes H or (C1-C4)-alkyl and m represents 2, 3 or 4, are described. They have hypotensive activity and/or ureter-relaxing activity.

Description

The invention relates to N-benzopyranyllactams of the formula I R >0H R ir in which R1 represents CN, N02, SOn-(^-C6)-alkyl or SOn-Ar; where n = 1 or 2, Ar represents phenyl which is unsubstituted or substituted by 1 to 3 identical or different (Ci_C2)-alkyl, (Cj^C^ alkoxy, halogen, trifluoromethyl, CN, N02, CO-(C1-C2)-alkyl or SOp- (Cx-C2) alkyl radicals, and p represents 1 or 2, R2 represents H, OH, (C1-C2)-alkoxy, (Cx-C2)-alkyl, halogen or NRSR®, where R5 and R6 are identical or different and represent H, (Cx-C2) -alkyl or (Cx-C2) alkylcarbonyl, R3 and R* are identical or different and represent alkyl having 1-4 carbon atoms, the abovementioned meanings of R1 and R2 may also be exchanged, and X represents a (CH2)m chain which is substituted by at least 1 and at most 2m-l (Cx-C2) -alkyl groups and may be interrupted by a heteroatom Y denoting 0, NR7 or S, and R7 represents H or (C1-C4)-alkyl, and m represents 2, 3 or 4, where the configurations at C3 and C4 are always opposed.
Halogen is taken to mean F, Cl, Br or I, preferably F and Cl.
Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzo(b]pyran V 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 abovementioned definition of X means that, in addition, the lactam ring contains at least one, but at most 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 case where R1, R2, R3 or R4 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 R1, R2, R3 and R4 have the abovementioned meanings and X represents a (CH2)ra chain which is substituted by a (CxC2) -alkyl group and may be interrupted by a heteroatom Y which represents O, S or NR7 where R7 denotes H or (C2-C4) alkyl, and where m represents 2, 3 or 4.
Additionally preferred compounds of the formula I are those in which R1 to R4 have the abovementioned meanings and X represents a (CH2)m chain which is substituted by a (Cx-C2)-alkyl group and where m represents 3 or 4.
Very particularly preferred compounds I are those in which R1 to R4 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 (Cx-C2)-alkyl group.
Especially preferred compounds are those in which R3-R4 have the abovementioned meanings and X represents a (CHJ,, chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the nitrogen atom of the lactam ring by a (Cx-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 of the chroman system.
Likewise very particularly preferred compounds I are those in which R1 represents CN or SO2-CH3 and R2 represents H, R3 and R4 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 (Cx-Cj) -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 R1 represents SO2-phenyl which is unsubstituted or substituted as mentioned above by 1 to 3 substituents, R2 represents H or OCH3, R3 and R4 are identical or different and represent (Ci-CJ 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 (Cx-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.
Preferred compounds are also those in which Rx-R4 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 (C1-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 which R1 represents CN or SO2-CH3 and R2 represents H, R3 and R4 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^-Cj) -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 R1 represents SO2-phenyl which is unsubstituted or substituted as mentioned above by 1 to 3 substituents, R2 represents H or OCH3, R3 and R4 are identical or different and represent (Cx-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 (Cj-Cj)-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, 21942201. They are summarized there under the following general formulae where R1, 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 the following may be mentioned: EP 107,423, EP 120,427, EP 076,075, EP 120,428 and EP-A-173,848.
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, 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.
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-position to one another for an optimum antihypertensive action. In contrast, a cis-arrangement leads to a significant weakening of the effect. Such transconf igures compounds also occur in the form of antipodes. It was possible to show, with reference to an example, that the (-)-antipode has a far stronger action than 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 compounds of the formula I. Surpris20 ingly, 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 substituent 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 substituents 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 previous35 ly known compounds by the fact that they additionally carry an aryl sulfonyl or aryl sulfoxy substituent as substituents in the benzo part, where aryl has 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 5 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 treat10 ment. 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 R1, R2, R3 and R4 have the abovementioned meanings, are reacted with lactams of the formula III H or b) compounds of the formula IV IV in which R1, R2, R3 and R4 have the abovementioned meanings , are reacted with lactams of the formula III, or c) compounds of the formula V •ί in which R1, R2, R3 and R4 have the abovementioned meanings , are acylated to give the compounds VI in which R1 to R4 and X are as defined above and Y denotes 10 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 R1 to R4 and X are defined as above, are oxidized 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 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 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 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 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 R1 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-benzo[b]pyran-4-ones of the formula VIII VIII .3 .0 are reacted with acid chlorides Ar-SO2-Cl in a fashion which is known per se in the manner of the Friedel-Crafts acylation, to give compounds of the formula IX in which R1 represents ArSOn (where Ar and n are as defined above) and in which R2, R3 and R4 are as defined above. These compounds IX are converted through reductions under standard conditions, such as by means of NaBH4 in methanol, into compounds X and the latter are subsequently subjected to elimination of water, for example by means of pyridine/phosphorus oxychloride, giving 2H-benzo[b]pyrenes of the formula XI: XI.
Compounds XI can easily be converted by standard methods into the epoxides IV or the bromohydrins II. If, in this reaction sequence, R2 denotes NH2 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 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 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 of about 75 kg. They are suitable for 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 (3R*, 4S*, 5'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-[2'oxo-5'-methyl-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol and (3R*, 4S*, 5'R*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-[2'oxo-5'-methyl-1-pyrrolidinyl)-2H-benzo[b]pyran-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 6cyano-trans-3-bromo- 3,4 -dihydro-2 , 2 -dimethyl-2Hbenzo [b] pyran-4-ol in 200 ml of DMSO 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-pyrrolidone are introduced. After stirring overnight at 20° the reaction mixture is poured into ice water, and the precipitate is reerystallized from methanol.
The reerystallized mixture is separated on a silica gel column using CH2Cl2/CH3OH (95:5). (3R*, 4S*, 5'S*)-6cyano-3,4-dihydro-2,2-dimethyl-4 -[2'-oxo-5'-methyl-1' pyrrolidinyl)-2H-benzo[b]pyran-3-ol is isolated and reerystallized repeatedly from ethanol.
Crystals of melting point: 239-240° NMR (ds-DMSO) CH3 signals δ 0.80 (3H, d) 1.17 (3H, s) 1.45 (3H, S) Analysis: calculated for C17H20N2O3 : 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-cyano-3,4-dihydro-2,2-dimethyl-4 -[2'-oxo-5'-methyl-1'10 pyrrolidinyl)-2H-benzo[b]pyran-3-ol is concentrated, is evaporated, and the compound is isolated on a silica gel column using CH2Cl2/Ch3OH (95:5).
Crystals of melting point: 190-192° (from ethyl acetate) NMR (d6-DMSO) CH3 signals δ 1.20 1.30 1.43 (3H, s) (1.5H, s) (4.5H, s) Analysis: calculated for C17H20N2O3: 300.37 calc. C, 67.98; H, 6.71; N, 9.33 % found C, 68.0; H, 6.7; N, 9.4 % Example 2 (-) -(3S, 4R, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4[2ΌΧΟ-5'-methyl-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol and (-)-(3S, 4S, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4[2 ' oxo-5' -methyl-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol v 6 g (0.2 mol) of 80 % NaH and 15 g (0.15 mol) of (R)-5methyl-2-pyrrolidone (see Rene Amstutz, Bjorn Ringdahl, Bo Karlen, 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-dihydro-2,2-dimethyl30 3,4-epoxy-2H-benzo[b]pyran 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 CH2C12/CH3OH 19:1 and the product is recrystallized from· ethanol. The first compound obtained is (-) -(3R, 4S, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-[2'oxo-5'-methyl-1'-pyrrolidinyl)-2H-benzo [b]pyran-3-ol.
Crystals of melting point: 184° αθ° = -27.8° c = 1 in ethanol.
As the 2nd, slower-moving, product, (-) -(3S, 4R, 5'R)-6cyano-3,4- dihydro-2,2- dimethyl-4 - (2 ' -oxo-5 ' -methyl-1 pyrrolidinyl)-2H-benzo[b]pyran-3-ol is obtained after additional crystallization from ethanol.
Crystals of melting point: 258° a£° = -86° (c=l, ethanol) Example 3 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4 -(2'-oxo-3'methyl-1-pyrrolidinyl)-2H-benzo[b]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-dihydro2,2-dimethyl-2H-benzo[b]pyran-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 % NaH and 8.6 g (0.084 mol) of racemic 3-methyl-2-pyrrolidone 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 suction, washed with a little water and dried.
The crude product is recrystallized twice from ethyl acetate/methanol and subsequently from dimethylformamide/ methanol. The diastereomer can be isolated in pure form in this way.
Crystals of melting point: 261-263° 4 5 NMR (d6-DMSO) CH3 signals: δ 1.19 (3H, s) 1.21 (3H, s) 1.45 (3H, s) Diastereomer A: The mother liquors from the above experiment are evapora10 ted, and the residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (9:1). Diastereomer A is separated off and recrystallized from ethanol.
Crystals of melting point: 210-211° NMR (d6-DMSO) CH3 signals: δ 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-420 (2'-oxo-5'-methyl-l-pyrrolidinyl) -2H-benzo [b] 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-2,2dimethyl-3,4-epoxy-6-methylsulfonyl-2H-benzo [b] pyran and 4 g (0.04 mol) of racemic 5-methyl-2-pyrrolidone in 50 ml 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 recrystallized from ethyl acetate.
Crystals of melting point: 190-193° NMR (d6-DMSO) CH3 signals: δ 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-3chlorobutyne in a manner which is known per se.
Melting point: 64-65° (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 180°.
Melting point: 107-108° (from diisopropyl ether) 3- Bromo-3,4-dihydro-2,2 -dimethyl - 6 -me thyl sulf onyl - 2Hbenzo[b]pyran-4-ol is obtained from 2.2- dimethyl-6-methylsulfonylchromene andN-bromosuccinimide in a 9:1 dimethyl sulfoxide/H20 mixture.
Melting point: 140-141° from diisopropyl ether 3,4-Dihydro-2,2 - dimethyl-3,4 -epoxy-6-met hyl sulf onyl- 2Hbenzo[b]pyran is obtained by reacting 3-bromo-3,4dihydro-2,2-dimethyl-6-methylsulfonyl-2H-benzo [b] pyran-4ol with sodium hydride in DMSO.
Melting point: 165° (from ethyl acetate) Example 5 (3R*, 4S*, 5'S*)-2,2-dimethyl-7-methoxy-6-phenylsulfonyl4- (2'-oxo-5'-methyl-1' -pyrrolidinyl)-2H-benzo[b]pyran3-ol and (3R*, 4S*, 5'R*)-2,2-dimethyl-7-methoxy-6phenylsulfonyl-4- [2' -oxo-5' -methyl-1' -pyrrolidinyl) -2Hbenzo[b]pyran-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 ( + )-5methyl-2-pyrrolidinone are added to a solution of 9.6 g of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzo[b]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 neutral, dried and subjected to chromatography on silica gel using the eluent toluene/methylene chloride/methanol 10:1:1. (3R*, 4S*, 5'R*)-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-4-[2'oxo-5'-methyl-1'-pyrrolidinyl)-2H-benzo[b]pyran-3-ol is eluted as the first major product: melting point: 21415°C; NMR (d6-DMSO) δ (ppm): 1.17; 1.27; 1.4 (s,s,s; 9H, 2.2- dimethyl and 5-methyl).
The slower-moving (3R*,4S*, 5'S*)-2,2-dimethyl-7-methoxy6-phenylsulfonyl-4-[2'-oxo-5'-methyl-l-pyrrolidinyl)-2Hbenzo[b]pyran-3-ol is obtained as the second major product.
Melting point: 244-245°C; NMR (d6-DMSO) δ (ppm): 0.73 (d, 3H, 5'-CH3) Preparation of the starting material: 3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzo[b]pyran-4-ol is obtained from 2,2dimethyl- 7-methoxy-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide/ H20.
Melting point: 202 - 203°C. 2.2- Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchromane by means of pyridine/phosphorus oxychloride in benzene.
Melting point: 140 - 141°C. 2.2- Dimethyl-4 - hydroxy - 7 - me t hoxy - 6 - phenyl sulf ony 1 c hromane is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl- 17 chroman-4-one by means of sodium borohydride in methanol.
Melting point: 146 - 147°C. 2,2-Dimethy1-7-met hoxy-6-phenylsulfonylchroman-4-one is obtained from phenylsulfonyl chloride, 2,2-dimethyl-75 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-phenylsulfonyl-4- (2'-oxo-5'-methyl-1-pyrrolidinyl) -2H10 benzo [b]pyran-3-ol and 3R*, 4S*, 5'R*-3,4-dihydro-2,2dimethyl- 6-pheny1sulfony1-4 - [2'-oxo- 5'-methyl-1pyrrolidinyl)-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*, 5'R*)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-[2'-oxo-5'-methyl-1-pyrrolidinyl)-2H-benzo[b] pyran-3-ol.
Crystals of melting point: 216-217° from ethanol NMR (d6-DMSO) 5'-CH3 signal: δ 0.48 (3H, pseudo-doublet). (3R*, 4S*, 5'R*)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-[2'-oxo-5'-methyl-1-pyrrolidinyl)-2Hbenzo[b]pyran-3-ol.
Crystals of melting point: 240-241°C from DMF/ethanol . .
NMR (dj-DMSO) 5'-CH3 signal: δ 1.27 (3H, d) ( ► In addition to the compounds described in the examples, the compounds of the formula I shown iri the table below can also be obtained according to the invention: 1. (3R, 4S, 5'S)- 3,4-dihydro-2,2-dimethyl-6-methylsulfonyl-4-[2' -oxo-5'-methyl-1-pyrrolidinyl)-2Hbenzo [b]pyran-3-ol, 2. (3R*, 4S* , 5'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-7methoxy-4- [2' - oxo-5 ' -methyl-l-pyrrolidinyl) -2Hbenzo[b]pyran-3-ol, 3. (3R*, 4S*, 4'S*) -6-cyano-3,4-dihydro-2,2-dimethyl-7hydroxy-4- [2' -oxo-4' -methyl-l-pyrrolidinyl) -2Hbenzo[b]pyran-3-ol, 4. (3R, 4S, 3'R)-3,4-dihydro-2,2-diethyl-6-nitro-4-(2'oxo-3' -methyl-l-pyrrolidinyl) -2H-benzo[b]pyran-3-ol, . (3R, 4S, 5' S)-7-amino-3,4-dihydro-2,2-dimethyl-6nitro-4-[2' -oxo-5' -methyl-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol, 6. (3R, 4S, 5'S) -3,4-dihydro-2-methyl-2-ethyl-6-phenyl sulfonyl-4-[2' -oxo-5'-methyl-l-pyrrolidinyl)-2Hbenzo[b]pyran-3-ol, 7. (3R, 4S, 3 ' S)-3,4-dihydro-2,2-diethyl-6-[p-nitro] phenylsulf onyl-4- [2' -oxo-3' -methyl-l-pyrrolidinyl] 2H-benzo[b]pyran-3-ol, . (3R*, 4S*,3'R*, 4'S*)-3,4-dihydro-2,2-dimethyl-6-[pcyano] -phenylsulfonyl-4- [2' -oxo-3' -methyl-4' -methyll-pyrrolidinyl] -2H-benzo[b]pyran-3-ol, 9. (3R*, 4S*, 5'S*) -3,4-dihydro-2,2-dimethyl-6- [pchloro] -phenyl sulf onyl-4- [2' -oxo-5' -methyl-l-pyrrolidinyl] -2H-benzo[b]pyran-3-ol, . (3R, 4S, 3'R, 4'S)-3,4-dihydro-2-methyl-2-propyl)6 [p-methoxy] -phenylsulfonyl-4- [2' -oxo-3'-methyl-4 ' ethyl-l-pyrrolidinyl]-2H-benzo[b]pyran-3-ol, 11. (3R*, 4S*, 4'R*)-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-4-[2 ' - oxo-4'-methyl-l-pyrrolidinyl]-2Hbenzo[b]pyran-3-ol, 12. (3R, 4S, 5'S)-3,4-dihydro-2,2-diethyl-6-[p-nitro] phenylsulfonyl-4-[2'-oxo-5'-methyl-l-pyrrolidinyl) 2H-benzo[b]pyran-3-ol, 13. (3R*, 4S*, 3'R*)-3,4-dihydro-2,2-dimethyl-6- [pcyano] -phenylsulfonyl-4- [2' -oxo-3' -methyl-l-pyrrolidinyl] -2H-benzo[b]pyran-3-ol, 14. (3R*, 4S*, 5'S*)-3,4-dihydro-2,2-dimethyl-6-[p19 chloro] -phenylsulfonyl-4-[2'-oxo-5'-ethyl-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol, . (3R*, 4S*, 5'S*)-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-4-[2'-oxo-5'-methyl -1-morpholinyl] -2Hbenzo[b]pyran-3-ol, 16. (3R*, 4S*, 6'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-4[2' -oxo-6'-methyl-1-piperazinyl]-2H-benzo[b]pyran-3ol, 17. (3R*, 4S*, 2' S*) -6-cyano-3,4-dihydro-2,2-dimethyl-4[4' -oxo-2' -methyl-3-thiazolidinyl] -2H-benzo[b]pyran3o1, 18. (3R*, 4S*, 6'S*)-6-cyano-3,4-dihydro-2,2-diethyl-4[2' -oxo-6' -methyl-1-piperidinyl] -2H-benzo[b] pyran-3ol.
Pharmacological 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 this stock solution were in each case freshly diluted with water.
Concentrations of 50 (100) , 30 (30) and 10 (10) Mg/ml were used for i.v. administration and 100 (100), 50 (60) and 30 (30) Mg/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 ED2S values were determined from the minima of the respective blood-pressure curves. a) (±)-(3R*, 4S*, 5'S*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2'-oxo-5'-methyl-1'-pyrrolidinyl)-2Hbenzo[b]pyran-3-ol (Compound from Example 1): ED25= 19 gg/kg (i.v.) ED2S= gg/kg (i.d.) b) (±)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2'oxo-1'-pyrrolidinyl-2H-benzo[b]pyran-3-ol (Example from J. Med. Chem. 1986, 29, 2194-2201) ED25= 42 gg/kg (i.v.) ED25 = 82 gg/kg (i.d.) In vitro influence of KC1-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 activity 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 C02) and having the following composition (mmol/1): NaCl 137, KC1 2.68, MgSO4 1.05, CaCl2 1.8, NaH2PO4 0.41, NaHCO3 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 χ 10'2 mol/1. 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 10*7 mol/1) and left to act for one minute before adding KCl. Subsequent washing was followed by v 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 contrac10 tions, 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 (χ) , the standard error of the mean (SEM) was calculated.
Compound mean height frequency, v k.v. n Results: of contractions k [%] [%] [%] {-)- (3R,4S,5'R)-6- 75 ± 8 89 ± 4 96 + 2 7 cyano-3,4-dihydro2,2-dimethyl-4- (2' oxo-5'-methyl-1' pyrrolidinyl)-2Hbenzo[b]pyran-3-ol from Example No. 2 ±)-(3R*,4S*,5'R*) - 69 ± 11 6-cyano-3,4-dihydro2,2-dimethyl-4- (2' oxo-5'-methyl-1' pyrrolidinyl)-2Hbenzo[b]pyran-3-ol from Example No. 1 86 ± 4 96 ± 1 6 +)-6-cyano-3,4-di- 8 ± 8 58 ± 5 61 + 7 7 hydro-2,2-dimethyltrans-4-(2-oxo-lpyrrolidinyl-2Hbenzo [b]-pyran-3-ol (from J. Med. Chem. 1986, 29 2194-2201) n = number of ureters Reference: P. SCHIANTARELLI and W. MURMANN.
Antispasmodic Activity of Rociverine on the Smooth Musculature of the Urinary Tract.
Arzneim.-Forsch./Drug Res. 30. 1102-1109 (1980)

Claims (13)

1. An N-benzopyranyllactam of the formula I \ Patent claims in which R 1 represents CN, N0 2 , SO„- (C i -C 6 ) -alkyl or SO n -Ar; where n = 1 or 2, Ar represents phenyl which is unsubstituted or substituted by 1 to 3 identical or different (C 1 -C 2 )-alkyl, (Ci-Cj-alkoxy, halogen, trifluoromethyl, CN, NO 2 , CO-(C 1 -C 2 )-alkyl or SO p -(C x -C 2 )-alkyl radicals, and p represents 1 or 2, R 2 represents H, OH, (C1-C2)-alkoxy, (Ci-Cj) -alkyl, halogen or NR S R 6 , where R 5 and R 6 are identical or different and represent H, (Ci-C 2 ) -alkyl or (C 1 -C 2 ) -alkylcarbonyl, R 3 and R 4 are identical or different and represent alkyl having 1-4 carbon atoms, the abovementioned meanings of R 1 and R 2 may also be exchanged, and X represents a (CH 2 ) ra chain which is substituted by at least 1 and at most 2m-l (C 1 -C 2 ) -alkyl groups and may be interrupted by a heteroatom Y denoting 0, NR 7 or S, and R 7 represents H or (Cx-Cj -alkyl, and m represents 2, 3 or 4, where the configurations at C 3 and C 4 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 1 , R 2 , R 3 and R 4 are as defined in claim 1, X is a (CH 2 ) m chain which is substituted by a (C x -C 2 ) alkyl group and may be interrupted by a heteroatom Y which represents 0, S or NR 7 where R 7 denotes H or (C 2 -C 4 ) -alkyl, and where m represents 2, 3 or 4 . 53. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following meaning: R 1 to R 4 are as defined in claim 1, X is a (CH 2 ) m chain which is substituted by a 10 (Cj-CJ -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: R 1 to R 4 are as defined in claim 1, 15 X is a (CH 2 ) 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 (Ci-Cj) -alkyl group. 5. A compound I as claimed in claim 1, wherein at least 20 one of the substituents or indices has the following meaning: R x -R 4 are as defined in claim 1, X is a (CH 2 ) m chain where m = 3 or 4 and which is substituted on the carbon atom neighboring the 25 nitrogen atom of the lactam ring by a -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
3. 0 one of the substituents or indices has the following meaning: R x -R 4 are as defined in claim 1, X is a (CH 2 ) m chain where m = 3 or
4. And which is substituted on the carbon atom neighboring the 35 nitrogen atom of the lactam ring by a (Ci-Cj) -alkyl group, the configuration of this carbon atom being opposite to that of the C-4 atom of the chroman system. > A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following ι meaning: R 1 denotes CN or SO 2 CH 3 , R 2 denotes H, R 3 and R 4 are identical or different and denote (C 2 -C 2 )-alkyl, and X denotes 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 x -C 2 ) alkyl group, the configuration of this carbon atom being the same as that of the C-4 atom in the chroman system. A compound I as claimed in claim 1, wherein at least one of the substituents or indices has the following meaning: R 1 denotes CN or SO 2 CH 3 , R 2 denotes H, R 3 and R 4 are identical or different and denote (Ci-CJ-alkyl, and X denotes 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 3 -C 2 ) alkyl group, the configuration of this carbon atom being opposite to that of the C-4 atom in the chroman system. A compound I as claimed in claim 1, wherein at least ♦ one of the substituents or indices has the following meaning: R 1 denotes S0 2 Ar. where Ar equals phenyl which is unsubstituted or substituted as defined in claim 1, R 2 denotes H or CH 3 , R 3 and R“ are identical or different and denote (Cj-Cj) -alkyl, and X denotes (CH 2 ) m where m = 3 or 4, substituted on the carbon atom neighboring the nitrogen atom of
5. The lactam ring by a (C x -C 2 ) -alkyl group, the configuration of this carbon atom being the same as that of the C-4 atom in the chroman system.
6. 10. A compound as claimed in claim 1, which is (-) -(3R,4S, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2'-oxo10 5'-methyl-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol.
7. 11. A compound as claimed in claim 1, which is (-)-(3S,4R, 5'R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2'-oxo5'-methyl-1'-pyrrolidinyl)-2H-benzo[b]pyran-3-ol.
8. 12. A process for the preparation of a compound I as 15 claimed in claim 1, which comprises a) reacting a compound of the formula II in which R 1 , R 2 , R 3 and R 4 have the abovementioned meanings, with a lactam of the formula III or b) reacting a compound of the formula IV IV, R 3 and R 4 have the abovementioned meanings, *· with a lactam of the formula III, or c) acylating a compound of the formula V in which R 1 , R 2 , R 3 and R 4 have the abovementioned meanings, 10 to give a compound VI o in which R 1 to R 4 and X are as defined above and Y denotes a leaving group, and cyclizing the latter to give a compound I, or d) oxidizing a compound of the formula VII Xa CS, in which R 1 to R 4 and X are as defined above, to give a compound I.
9. 13. The use of a compound of the formula I as claimed in claim 1 for the production of a medicament for 5 treating high blood pressure. i' . ' · · *.
10. 14 . The use of a compound of the formula I as claimed in any of claims 6 ; , ;8 and 10, for the production of an agent for relaxation of the.uVeter. A. t j
11. 15. An N-benzopyranyllactam of formula I given 10 and defined in claim 1, substantially as hereinbefore described and exemplified.
12. 16. A process for the preparation of an N-benzopyrranyllactam of the formula I given and defined in claim 1, substantially as hereinbefore described 15 and exemplified.
13. 17. An N-benzopyranyllactam of the formula I given and defined in claim 1, whenever prepared by a process claimed in claim 12 or 16. 18. Use according to claim 13, substantially as here- 20 inbefore described. 19. Use according to claim 14, substantially as here- inbefore described. F . R. KELLY & CO. » J AGENTS FOR THE APPLICANTS. I
IE29588A 1987-02-04 1988-02-03 Alkyl-substituted N-benzopyranyllactams, a process for their preparation, their use, and pharmaceutical preparations based on these compounds IE60932B1 (en)

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