GB2168969A - 1,4-dihydro pyridines - Google Patents
1,4-dihydro pyridines Download PDFInfo
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- GB2168969A GB2168969A GB08520485A GB8520485A GB2168969A GB 2168969 A GB2168969 A GB 2168969A GB 08520485 A GB08520485 A GB 08520485A GB 8520485 A GB8520485 A GB 8520485A GB 2168969 A GB2168969 A GB 2168969A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
1 GB 2 168 969 A 1
SPECIFICATION
Heterocyclic compounds This invention relates to heterocyclic compounds possessing pharmaceutical activity, more particularly to 5 1,4-dihydropyridines, processes for preparing them and pharmaceutical compositions containing them.
In one aspect this invention provides a compound of formula Ar 10 R1 02 C C02 R 2 10 3'1" M B ' N 3 A 15 or a salt thereof; wherein: Ar is an optionally substituted aryl radical; R represents hydrogen or an op tionally substituted alkyl or aralkyl group; R, and R2 are the same or different and are selected from hy drogen and saturated or unsaturated, cyclic or acyclic aliphatic hydrocarbon residues optionally substitute by one or more groups selected from halogen, CH, carboxy, CN, alkoxy, alkylthio, aryloxy, 20 alkoxycarbonyl, amino, substituted amino, and optionally substituted aryl; A represents a group of formula -XR3 wherein X is (i) a group of formula -(CHR6)p-Y-(CHR7) -or (ii) a group of formula -(CHR6) -0-(CHR7)- s 25 25 in which formulae: Y represnets -S-, NR11 or a direct bond, p and q each represent 0, 1 or 2 providing that p and q do not both represent zero when Y is a direct bond; one of r and s represents 0, 1 or 2 and the other is zero; R6, R7 and R11 independently represent hydrogen or lower alkyl, -and R3 is an optionally substituted nitrogen ring heteroaryl radical optionally containing other ring heter- oatoms selected from oxygen, nitrogen or sulphur B represents hydrogen, carboxyl, lower alkoxycar- 30 bonyl, lower alkyl optionally substituted by lower alkoxy, lower alkoxycarbonyl, carboxy or amino, or amino optionally substituted by one or two lower alkyl groups.
By the term aryl when used as a group or part of a group (e.g. aryloxy, arylalkyl) is meant any monovalent carbocyclic or heterocyclic radical possessing aromatic character and includes groups having 5 to 10 ring atoms such as.phenyl, naphthyl, pyridyl (e.g. 2-, 3-or 4-pyridyl), thienyl (e.g. 2-thienyl) furyl (e.g. 35 2-furyl), quinolyl (e.g. 2-, 3- or 4-quinolyl), isoquinolyl (e.g. 2,3- or 4- isoquinolyl) and benzimida-zolyl.
Preferred heteroatoms are nitrogen, oxygen and sulphur. Examples of heterocyclic aromatic rings con taining two heteroatoms are imidazolyl, e.g. 1-imidazolyl, thiazolyl e.g. 2-thiazolyl and pyrimidyl e.g. 2 pyrimidyl.
The term alkyl when used to signify a group or part of a group such as arylalkyl or alkyloxy means any 40 straight or branched satufated aliphatic hydrocarbon especially those having 1 to 6 carbon atoms, e.g. 14 carbon atoms, or cyclic saturated aliphatic hydrocarbons especially those of 5 to 7 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl and cyclohexyl.
By the term 'optionally substituted',is - meant optional substitution on carbon atoms by one or more substituents, e.g. substituents commonly u sed in pharmaceutical chemistry, e.g. halogen (e.g. CI,Br,F), 45 alkyl,,alkyloxy, haloalkyl (e.g. CF,,'),.or-haloalkoxy (e.g. CHF,O-, CF,, CH,O-), NO,, NH,, CN, alkylamino, di alkylamino, carboxy, alkyloxycarb, onyl, acyl, acylamino, aryl (e.g. phenyl) or aminoalkyl.
Examples of the group R are grous as described above in connection with alkyl, aryl and arylalkyl and include hydrogen, methyl, ethyl, n-propyl, isopropyl and benzyl. Preferably R is hydrogen.
The groups R1 and R2 can be independently hydrogen, or saturated or unsaturated acyclic hydrocarbon 50 chains of 1 to 6 carbon atoms, e.g. lower alkyl or alkenyl, optionally substituted by aryl of 5 to 10 ring atoms, lower alkoxy, arnino, diloweralkylamino, carboxyl or lower alkoxy6arbonyl.
Examples of R, and/or R2 are methyl, ethyl, n-propyl, isopropyl, butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, dimethylaminoe- thyl, 2-carboxy-ethyl, ethoxyca rbonyl m ethyl. When R, or R2 is alkyl substituted by optionally substituted 55 aryl (including heteroaryl) examples are benzyl, pyridylmethyl or -ethyl (e.g. 3-pyridylmethyl), imidazolyl methyl (e.g. 1-imidazolyl-methyl) or imidazoylethyl.
Preferred values for R, and/or R2 are methyl and ethyl.
Examples of R3 are imidazolyl (e.g. 1 or 3-imidazolyl), pyridyl (e.g. 2 or 3-pyridyl), thiazolyl (e.g. 2-thia zolyl), pyrrolyl (e.g. I-pyrrolyl) or bicyclic rings such as benzimidazolyl (e.g. 1-benzimidazolyl), quinolyl 60 (e.g. 2-or 4-quinolyl), isoquinolyl (e.g. 1- or 4-isoquinolyl), imidazopyridyl (e.g. 5-imidazo[1,5-al-pyridyl).
Preferred values are 1-imidazolyl, 3-pyridyl and 5-imidazo[1,5-al-pyridyl.
Examples of X are independently -NH; -0-; -S-; -CH,-; -CH(CH,)-; -OCH2-; CHO; -(CH,)2-0-' CH2CH(CH,)-; CH(CH,)CH,-; groups of formula -CH2_Z_CH2_1 -CH2-Z-(CH2)2-, - (CH2) -Z-CH,,- where Z is S, NH or a direct bond. 65 2 GB 2 168 969 A 2 Examples of B are H-, CH,-, NH,-, NMe2-, NHMe-, NH2CH,-, CH3CH2-, CH,OCHr, CH,OOC-, HOOC-, CH30OCCH,- and HOOCCH2_. Preferred examples of B are CH,- and NH2.
Preferred examples of X are -CH2-, -(CH2)2-, -CH(CHj-, -CH,CH(CHj-, CH(CH,)CH,-, -CHO-, -CH,NH- and - CH2-S_.
5 Examples of Ar are groups mentioned above for the definitions of aryl and included in the preferred 5 values are 2- andlor 3-substituted phenyl groups, e.g. 2-andlor 3- nitrophenyl; 2,3-dichlorophenyi; 2-tri fluoromethyi-phenyl, pentafluorophenyl, naphthyl (e.g. l-naphthyl), pyridyl (e.g. 2-pyridyl), halopyridyl (e.g. 2-chloropyrid-3-yi), benzimidazolyl (e.g. 4- or 7-benzimidazolyl.
Particularly preferred compounds provided by this invention have formula la:
10 10 R12_ R 11 15 R 1 02C ', C02 R 2 15 13., 3 R 5 1 R "I X -N N 20 1 \---i (Ia) 20 R wherein R, R, and R2 have the meanings given above, RG is H or lower alkyl, X3 is -CH2-, -CH,NHCH 2-, - CH2NH(CHI-CH2CH2-, -(CHj 0, or -CH20-, -CH(CHj-; R" and R12 are each selected from hydrogen, nitro, 25 halo or trifluoro-methy], and R13 is NH2- or lower alkyl especially methyl; or a salt thereof, or an optically 25 active isomer thereof.
In formula la preferably R is hydrogen.
Examples of R, are H, Me or Et. Examples of R2 are Me and Et. When R,' is hydrogen examples of R12 are 3-nitro, 2-trifluoromethyl. Examples of R" and R12 when substituents are 2,3-dihalo, e.g. are 2,3-dich- 30 loro, 3-nitro-2-halo and 3-halo-2-nitro. 30 The term "lower" as used herein denotes 1 to 6 carbon atoms.
Other preferred compounds are compounds of formula]a in which 1imidazolyl is replaced by a pyri dine ring, preferably pyrid-3-yt.
The compounds of formula 1 possess pharmaceutical activity in particular antihypertensive andlor hy 35 potensive activity when tested on warm blooded animals and hence are indicated for the treatment of 35 high blood pressure. In addition since the compounds of this invention antagonise calcium movement into the cell they,are also vasodilators and useful in the treatment of a variety of cardiac conditions such as heart attacks, angina pectoris, cardiac arrythmias, cardiac hypertrophy and coronary vasospasm. Fur thermore the compounds of formula 1 also inhibit blood platelet aggregation and inhibit thromboxane 40 synthetase. These latter activities in combination with their antihy- pertensive properties makes these 40 compounds potentially very useful for the treatment of cardiovascular disorders, especially thrombosis.
The compounds of formula 1 were tested for anti hypertensive activity by the following standard proce dure:
The blood pressures of male or female spontaneously hypertensive rats are measured in a 370C con stant temperature housing by means of a tail cuff. Rats with systolic pressures below 155 mmHg are 45 discarded. Groups of rats are dosed orally with the test substance in a suitable vehicle or with vehicle alone. systolic pressures are recorded before dosing and at selected time points afterwards. Heart rates are derived from caudal artery pulses. Results are analysed statistically by means of 2 way analysis of variance (within group).
50 In this procedure representative compounds of the invention gave the results shown in the following 50 Table:-
3 GB 2 168 969 A 3 Compound Dose Level Blood Pressure (mmol/kg po) as % of pre-dose level (time.
tafter dosing) 5 5 t=2hrs 6 hrs 24 hrs 1,4-Dihydro-2-(imidazol- 0.15 42% 46% 85% 1 -ylmethyl)-6-methyl-4 10 (3-nitrophenyl)pyridine 0.03 48% 62% 105% 10 -3,5-dicarboxylic acid 0.003 65% 70% 83% 3-ethyl 5-methyl diester 1,4-Dihydro-2-[2-imida- 0.15 35% 42% 74% 15 zol- 1 -yl)-ethyl 1-6-m ethyl15 4-(2-nitrophenyl)pyridin- 0.03 63% 99% 105% ine-3,5-dicarboxylic acid diethyl ester 20 20 Calcium antagonist activity was demonstrated by examining drug effect on the response of isolated rat portal vein to increasing calcium ion concentration in vitro. In this test a molar concentration of 2 x 10-7M of 1,4-dihydro-2-(imidazol-1-ylmethyl)-6-methyI 4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-ethyl 5 methyl ester was required to reduce the response by 50%.
25 Compounds of formula I were tested for their ability to inhibit blood platelet aggregation by a modifi- 25 cation of the procedure of Fantl, Australian J.Exp.Biol.Med.Sci. 45, 355- 62 1967.
Since platelet aggregation is the initial step in thrombus formation it is considered that compounds which prevent aggregation or reduce platelet adhesiveness may inhibit the initiation of the atheroscler otic process. The effect of drugs on adhesiveness is measured in platelet- rich plasma containing a small amount of arachidonic acid which markedly increases aggregation in vitro and may be a physiological 30 agent for doing so in vivo. The actual test procedure used in described below.
New Zealand White rabbits (2.5-3kg) are anaesthetised with an injection, via the marginal ear vein, of sodium pentobarbitone 30-40 mg/kg. The carotid artery is cannulated and blood (100-150 ml) is with drawn into 50 ml syringes containing 3.8% sodium citrate (Ratio blood: citrate = 9:1).
35 Blood is centrifuged at 200g (1500 r.p.m.) for 10 minutes at 5'C. and the platelet rich plasma (PRP) 35 removed. The platelets are then kept at room temperature in a screw topped plastic centrifuge tube for the duration of the experiment.
A twin channel platelet aggregometer - (HU aggregometer, A. Browne Ltd, Leicester, UK) is used. 1.0 ml aliquots of PRP are prewarmed for 5-10 minutes and stirred continuously at 1100 rpm. Aggregation is 40 induced by addition of 250lLM arachidonic acid, (8KI volume) to the PRP samples. The aggregometer out- 40 put is set at maximum and the chart recorder sensitivity is altered to give a full scale deflection to this arachidonic acid response.
Control responses are recorded as the maximum deflection obtained after addition of 250RM arachi donic acid.
45 PRP samples are preincubated for 1 minute with the test compounds followed by arachidonic acid ad- 45 dition. The maximum deflection after the addition of arachidonic acid is then recorded. All drugs are screened initially at 10-4M (final concentration), i.e. 10d of a 1 X 10- 2M stock solution of the drug dis solved in distilled water is added to the PRP.
Dazoxiben, a thromboxane synthetase inhibitor (Randall, M.J. et al Research 23 145-16 1981) is used as 50 a positive control and all test components are compared with Dazoxiben. The activity of the test compound is expressed as the ratio IC, Dazoxiben/1C,, Test where IC,,) is the dose required to inhibit the A.A.
induced aggregation by 50%. The greater the ratio the more potent the compound relative to Dazoxiben.
4 GB 2 168 969 A 4 Compound Inhibition of blood platelet aggregation potency ratio (dazoxiben 5 11 5 1,4-Dihydro-2-[2-(imidazoI-1 -yl)ethyl1-6 methyl-4-(2-nitrophenyl)pyridine-3,5- 0.79 dicarboxylic acid diethyl ester 10 10 1,4-Dihydro-2-(imidazol-1-ylmethyl)-6methyl-4-(3-nitrophenyl)pyridine-3,5- 1.2 dicarboxylic acid 3-ethyl 5-methyl diester 1,4-Dihydro-2-[2-(imidazol-i-yi)ethyll-6-methyl-4-(2-nitrophenyl)- 1.64 pyridine-3,5-dicarboxylic acid dimethyl ester 20 20 1,4-Dihydro-2-methyl-4-(3-nitrophenyl)-6[(3-pyridyloxy)methyllpyridine-3,5- 1.1 dicarboxylic acid 5-ethyl-3-methyl diester 25 25 Compounds possessing thromboxane synthetase inhibitory activity are useful in the treatment or pre vention of diseases responsive to the inhibition of thromboxane synthetase especially carbiovascular dis orders such as thrombosis, atherosclerosis, cerebral ischaernic attacks; and angina pectoris; peripheral vascular diseases and migraine. The compounds of formula I were tested for their ability to inhibit 30 thromboxane production by the following standard test:
a) Generation of thromboxanes Blood (approx. 75 ml) is obtained from an anaesthetised rabbit and centrifuged at 200g for 10 minutes to obtain platelet rich plasma (PRP). An aliquot of PRP is incubated for 10 minutes at 370C in the presence 35 of vehicle or drug. Platelet aggregation is induced by the addition of adenosine diphosphate and adren alin. The tubes are incubated for 3 minutes, centrifuged at 10,000 for 3 minutes and a 50 ml aliquot of the supernatant taken for radio-immunoassay of thromboxane B, (TxB2).
40 b) Radio-immunoassay of TxB2 40 The total incubation volume is 150L containing 501LI of 3H - TxB, (0.005 I.LCi), 50 m( of sample or au thentic TxB2 ranging from 5 to 300 pg per tube as standards and 50d of rabbit anti-sera to TxB2 (in a concentration which will bind 50% of H-Tx82). After incubation for 1 hour at room temperature the tubes are further incubated for 16-20 hours at 4C. 1 ml of dextran-coated charcoal is then added to the tubes which are further incubated on ice for 10 minutes. Following the incubation the samples are centrifuged 45 at 10,000g for 10 minutes and 500 ml of the supernatant added to 6 ml of scintillation cock-tail. Measure ment of the radioactivity in the supernatant quantifies the amount of [3H]-TxB, bound by the antibody.
The concentration of unlabelled TxB, in the sample is then determined from a linear standard curve.
In the above mentioned test the representative compounds of Examples 1, 2 and 5 gave IC, values of 50 5.0; 2.3 and 12.3 [LM respectively. In the same test the anti hypertensive agent nifedipine had an 50 IC,,,>1000LM. IC,,, values represent the concentrations of drug which achieve 50% inhibition of TxB,.
Some compounds of formula I have also been found to possess Phospholipase A, (PLAJ inhibitory activity and hence are also indicated for use as antiinflammatory and antiallergic agents. Of particular interest for this activity are compounds of formula I wherein Ar represents an aryl radical having a 2-nitro substituent. For example the compound of Example 2 produced a 77% inhibition of PLA, activity at a 55 concentration of 100pM. PLA, activity was assayed by a procedure based on Franson, R.C., Chapter 12.
Intracellular Metabolism of Ingested Phospholipids. Liposomes: from Physical Structure to Therapeutic Applications. North-Holland Biomedical Press, 1981, pp 349-380 and involving measuring the hydrolysis of E.coli membrane phospholipids and the release of free [1-14]oleic acid from the C-2 position of phos 60 pholipids by human platelet PLA, 60 This invention also provides processes for preparing the compounds of formula 1. In general both the compounds of formula I and intermediates of analogous structure may be prepared by processes which are known or are analogous to known processes; see for example Drugs of the Future, VoLVI, No. 7, 1981 pps 427-440. A first general process for preparing compounds of formula I as hereinbefore defined wherein B is hydrogen, lower alkoxy-carbonyl, carboxyl, or optionally substituted lower alkyl with the 65 GB 2 168 969 A 5 provisos that a) r cannot be zero and b) when Y is -S- or -NRII- then p is 1 or 2, comprises reacting corresponding compounds of formula 5 R i 02C Ar 5 10 1 il 10 T 0 R NH., III ,, CO., R 2 20 0 '00"1- T 2 IV 20 wherein Ar, R, R1 and R2 are as defined above, and one of Ti and T2 is A, the other is B wherein A and B are as defined immediately above. The process is conveniently carried out by heating, e.g. at reflux, in an 25 inert solvent preferably polar such as ethanol, toluene, dimethylformamicle, isopropranol, acetonitrile.
A second general process for preparing compounds of formula I as hereinbefore defined and subject to provisos a) and b) as in the first process mentioned above, comprises reacting a corresponding compound of formula 11 as shown above with a corresponding compound of formula 30 O,R 2 30 ,- " 24 (V) 35 RHN T 35 wherein Ar, R, R, and R2 are as defined above, and one of T, and T2 is A, the other is B providing that when T2 is A then T, cannot be optionally substituted amino. This process may conveniently be carried out by heating e.g. at reflux in an inert solvent (preferably polar) such as ethanol, acetonitrile, isopro- pranol, toluene or dimethylformamide.
In yet a further process compounds of formula I wherein provisos (a) and M above apply may be prepared by reacting a compound of formula ArCHO with corresponding compounds of formula VI and V shown below 45 R 1-0 2 CO 2 R 2 45 and 50 1 1-'1 1k1 I- i ' 2 50 1 T o RNII T wherein Ar, R, R, and R2 are as defined above and one of T, and T2 is A, the other B, providing that when T2 is A then T, cannot be optionally substituted amino. Such a process may be carried out by heating the 55 reactants, e.g. at reflux, in an inert solvent (preferably polar) such as ethanol, acetonitrile, isopropranol, 55 toluene or dimethylformamide.
Compounds of formula I may be prepared by reacting corresponding compounds of formula Ar R 1 02 C i I C02 R 2 B N'_ (CHR 6) Z i (VII) I R V 6 GB 2 168 969 A 6 and Z 2 (CHR 7) W R 3 5 (VIII) 5 in which formulae B,R,W,R2,133,1R6 and R7 are as defined above, one of ZI and Z2 is halogen or a sulphonyloxy group; the other of ZI and Z2 is -YH, Y-, OH or 0- as appropriate (wherein Y is as defined above) and v and w are each 0, 1 or 2 with the provisos that (i) when v is 2 and Z2 is YH or Y then ZI can also represent dialkylamino, e.g. -NMe, or a quaternary 10 ammonium group, e.g. -NMe,- 1; and (ii) when one of Z1 or Z2 is OH or 0- then one of v and w is 0.
The reaction may be carried out in an inert solvent in the presence of base, e.g. K2C03 or a tertiary amine e.g. triethylamine Anions of the requisite starting materials may be generated by the usual meth- 15 ods known in the art and reacted. Examples of sulphonyloxy are alkyl or aralkyl-or aryi-sulphonyloxy,e.g. 15 tosyloxy or mesyloxy.
The starting materials of formula V11 wherein ZI is halogen, sulphonyloxy as defined above may be prepared by known methods, e.g. from corresponding compounds of formula 20 R 1 02 c Ar ro 2 R 2 20 r 1 1 6 N (CHR) OH 25 B 1 v (IX) 25 R by methods known for the conversion of OH to halogen or sulphonyloxy. Compounds of formula Vill 30 wherein v = 0 may be prepared by reacting a compound of formula X 30 R 1 02 c 35 (X) 35 B NIM wherein R, R, and B are as hereinbefore defined with compounds of formulae 40 40 2I.r CO R 2 2 1 (Xl) 45 C02 alkyl 45 in which formula Ar and R2 are as defined above.
Compounds of formula]X wherein v is 1 or 2 may be prepared by reacting a compound of formula 50 Ar C02 R 2 50 (XTI) 55 0 (CHR 6) v OH 55 wherein v is 1 or 2 and Ar and R2 are as defined above with a compound of formula (X) as hereinbefore defined.
Compounds of formula V11 wherein v is 2 and ZI is -Walkyl)2 or a quaternary ammonium group may be prepared by performing a Mannich reaction on a compound of formula 7 GB 2 168 969 A 7 Ar R 1 02C C02 R 2 5 B 1 N CH 5 1 3 1 (XIII) R using formaldehyde and secondary amine and if required reacting the product with an alkyl halide. Com- 10 pounds of formula VII wherein Z1 is Y- or 0- may be prepared by known methods. For example, when Z, 10 is -OH, -NHIR11 or -SH anions may be formed in the presence of a strong base, e.g. an alkali metal hydride such as NaH or BuLL When Y is a direct bond carbanions may be prepared from the corresponding halo compound using for example, lithium diisopropylamine or BuILL If any of the aforementioned reactions reactive substituent groups may be protected if susceptible to 15 the reaction conditions and deprotected afterwards.
Compounds of formula 1 wherein R, is other than hydrogen may be prepared by alkylating a compound of formula 1 wherein R is H in the presence of a strong base, e.g. an alkali metal hydride, with a compound of formula R halogen where R is as defined above other than hydrogen.
Compounds of formula 1 having ester functional groups, e.g. cyanoethyl- or t-butyl-ester, may be hy- 20 drolysed, selectively if appropriate, to give compounds of formula 1 having carboxyl groups. Alternatively 20 carboxyl groups can be esterified.
The compounds of formula 1 possess one or more asymmetric centres and hence optical isomers and mixtures thereof are possible. All such isomers and mixtures thereof are included within the scope of this invention. Where any reaction process produces mixtures of such isomers standard resolution techniques 25 may be applied to separate a specific isomer.
In any of the aforementioned reactions compounds of formula i may be isolated in free base form or as acid addition salts as desired. Examples of such salts include salts with pharmaceutically acceptable acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, succinic, malonic, formic, maleic acid or organosulphonic acids such as methane sulphonic ptolyi sulphonic acids.
When acidic substituents are present it is also possible to form salts with bases e.g. alkali metal (such as sodium) or ammonium salts. Such salts of the compounds of formula 1 are included within the scope of this invention.
When basic substituents are present then quaternary ammonium salts may be formed by quaternizing 35 with an aikylating agent such as alkyl, or alkyl halides.
Starting materials for the processes described herein are known compounds or can be prepared by analogous methods for known compounds.
This invention also provides pharmaceutical compositions comprising a compound of formula 1 or a pharmaceutical iy acceptable salt thereof.
40 For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a com- 40 position, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admix 45 ture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier hav45 ing the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredi ent. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax 50 and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient 50 with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers, which is thus in association with it. Similarly cachets are in cluded.
Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
55 The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as 55 sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. Other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.
Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose 65 8 GB 2 168 969 A 8 of composition may be varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the com pounds in the absence of carrier where the compounds are in unit dosage form. Based on the results from animal studies the dosage range for the treatment of humans using a compound of formula 1 will 5 be in the range from about 5 mg to 500 mg per day depending on the activity of the compound. 5 The following Examples illustrate the invention and methods for preparing compounds of the inven tion. Since the final product may be sensitive to light, light should be excluded whenever possible during and after synthesis of compounds of the invention.
10 Example 1 10 1,4-Dihydro-2-(imidazoll-ylmethyl)-6-methyl-4-(3-nitro-phenyl)pyridine- 3,5-dicarboxylic acid 3-ethyl 5 methyl diester A mixture of methyl 2-(3-nitrobenzylidene)acetoacetate (2.5g. 0.01 mol), ethyl 4-(imidazol-l y1)acetoacetate 39,50% excess), ethanol (20 m[) and concentrated 0.880 ammonia (1 m]) was stirred for 1 hour and refluxed for 5 hours. The solvent was evaporated under reduced pressure and the residue chromatographed on alumina (Act 1, neutral 120g) using CHCl, initially as eluent to remove by-products and then 10% MeOH in CHCl. to elute the title compound.
Treatment of this in ethanol with ethanolic HCl gave the hydrochloride, hemihydrate salt of the title compound, m.p. 144-146'C.
20 20 Analysis:
C,H,2H,0,HC1.112H20 requires C, 53.45; N, 5.13; N, 11.87% Found: C, 53.46; H, 4.86; N, 11.67%.
25 Example 2 25 1,4-Dihydro-2-[2-(imidazol-l-yl)-ethyll-6-methyl-4-(2nitrophenyl)pyridine-3,5-dicarboxylic acid dlethyl es ter a) A mixture of 1,4-dihydro-2,6-dimethy]-4-(2-nitro-phenyf)pyridine-3,5- dicarboxylic acid diethyl ester (7.5g, 0.02 mol), dimethylamine hydrochloride (2.449, 0.03 mol), paraformaldehyde (0.99, 0.03 mol), 30 ethanol (35 m]) and 4 drops of concentrated HCl was heated at reflux for 10 hours. The solvent was then 30 evaporated and the residue partitioned between dilute aqueous hydrochloric acid and ethyl acetateldie thyl ether. The aqueous acid phase was separated, basified with ammonia and back extracted into ether.
The ether extract was dried and evaporated to give an oil. This was eluted down an alumina (2509, Merck Act 1) column using CHCl, as eluent to give 49. of 1,4-dihydro-6- methyl-2-(2-dimethylaminoethyi)4-(2-nitrophenyi)-pyridine-3,5-dicarboxylic acid diethyl ester which crystallised on standing and was re- 35 crystallised from diisopropyl ether (10 m]) to give 1.8g of crystalline compound.
b) A mixture of the product of step (a) above (2.15g, 5mmol), imidazole (2.72g, 40 mmol) and chloro benzene (50mi) was heated at reflux for 3 days. The solution was then cooled, washed thrice with water, dried and evaporated. The residue was recrystallised from ethyl acetate to give the product 1.49 (61.6%) 40 m.p. 195-8'C. The base was suspended in hot ethanol (5 mi) and maleic acid (0.3759, 5% excess) added 40 to give a clear solution. On cooling in ice the crystalline maleic acid salt of the title compound separated and was collected by filtration (1.559).
Recrystallisation from ethanol (6m]) gave 1.3g mp. 140-1410C.
Analysis: 45 C,,H,,N40C,H40, requires C, 56,84; H, 5.30; N, 9.82% Found: C, 57.10; H, 5.60; N, 9.50%.
Example 3
50 1,4-Dihydro-2-[2-(1-imidazolyl)ethyll-6-methyl-4-(2nitrophenyl)pyridine-3,5-dicarboxylic acid dirnethyl 50 ester In a manneranalogous to Example 2(b) with exclusion of light, 1,4dihydro-6-methyi-2-(2-(dimethylaminoethyi)-4-(2-nitrophenyi)pyridine-3,5-dicarboxylic acid dimethyl ester (1.619), 4 mmol) was reacted with imidazole (2.179, 32 mmol) in the presence of chlorobenzene (40 mi) to give the tile compound (0.399) 55 This was suspended in warm isopropyl alcohol (4 mi), maleic acid (0.1 13g), 1.05 equiv.) was added and 55 the mixture stirred at room temperature for 2 hours to give 0.46 g of the maleic acid salt, mp 176-70C.
Analysis:
C21H22NA.C^04 requires (55.35; H, 4.83; N, 10.33% 60 Found: C, 55.71; H, 5.02; N, 10.03%. 60 Example 4
1,4-Dihydro-2-methyl-4-(3nitrophenyl)-6-f(3-pyridylaxy) methyllpyridine-3, 5-dicarboxylic acid 5-ethyl-3 methyl diester 65 Ethyl 2-(3-nitrobenzyiidene)acetoacetate (6.47g. 0.026mol), ethyl 3oxo-4-(3-pyridyloxy)butanoate (5.89, 65 9 GB 2 168 969 A 9 0.026 moO and 0.88 ammonia (2.5 mi) in ethanol were refluxed for 7 hours. The solvent was removed under reduced pressure and the residue partitioned between 2N hydrochloric acid and diethyl ether. The aqueous acid was extracted with chloroform and this was washed with dilute ammonia solution, dried (MgSO,) and evaporated. The residue was purified by chromatography on silica with chloroform as 5 eluent to give as a first major product the title compound. This was dissolved in ethyl acetate and treated 5 with ethanolic HCl. Evaporation to low volume followed by addition of diethyl ether gave the hydro- chloride salt of the title compound (4.15g). mp. 201-2OWC.
Analysis:
10 C2,1-123N307MC1 requires C, 56.39; H, 4.94; N, 8.58% 10 Found: C, 56.53; H, 5.22; N, 8.91%.
Example 5
2-[2-(1-Benzimidazolyl)ethyll-4-[2,3-dichlorophenyll-1, 4-dihydro-6methylpyridine-3,5-dicarboxylic acid dimethylester 15 A mixture of 4-(2,3-cl ich 1 o roph enyi)-1,4-d i hyd ro-6-methyi-2-(2-(d i methyl am i noethyl)pyrid i ne 3,5-d ica r boxylic acid dimethyl ester (2.14g, 5 mmol), benzimidazole (2.36g, 20mmoi)1,8-diazabicyclo[5.4.Olundec-7- ene (0.75 9, 5 ffimol) and chlorobenzene (50 m] was heated at reflux for 24 hours. The solution was then diluted with chloroform (50 mi) washed with water dried and evaporated. The residue was triturated 3 20 times with warm toluene to give the title compound 1.5g. This was suspended in methyl acetate (25 mi) 20 and acidified with ethanoiic HCl to precipitate the hydrochloride (1.5g.) which was recrystallised from 1:1 aqueous methanol mp 155-158'C.
Analysis:
25 C2,H23C'2N.04.HC1.1/2H20 requires: C,55.01; H,4.62; N, 7.70% 25 Found: 2,54.96; H, 4.46, N, 7.50%.
Example 6
4-(2,3-Dichlorophenyl)- 1,4-dihydro-2-methyl-6-(2-[2-methyl(limidazolyl)lethyl)pyridine-3,5-dicarbo xylic 30 acid, dimethyl ester. 30 A mixture of 4-(2,3-dichiorophenyi)-1,4-dihydro-6-methy]-2-(2dimethylaminoethyl)pyridine 3,5-dicarbox ylic acid dimethyl ester (2.14g, 5mmol), 2-methylimidazole (1.64g, 20mmol), 1,8-diazabicyclo[5.4]undec-7 ene (0.75g, 5mmol) and chlorobenzene (50mi) was heated at reflux for 24hours. The solution was cooled, diluted with chloroform (25m]), washed with water (100mi), dried and evaporated. The residue was chro 35 matographed on silica gel (50g, Act i) using chioroform-methanol as eluent to give the title compound. 35 This was suspended in methanol (10mi) and acidified by addition of maleic acid (0.5g, 5% excess) to give a clear solution which was then diluted with ether (10mi) to precipitate the crystalline maieate salt 1.65mp 197-198'.
40 Analysis 40 C.21-12X12N304.C,H40, requires: C, 53.80, H, 4.69; N, 7.24% Found: C, 54.15, H, 4.75, N, 6.97%.
Example 7
45 4-(2,3-Dichlorophenyl)-1,4-dihydro-2-[2-(1-imidazolyl)-ethyll-6methylpyri dine-3,5-dicarboxylic acid, di- 45 methyl ester In a manner analogous to Example 6 but using imidazole instead of 2- methylimidazole the title com pound was prepared as the maleate salt, mp 180-182'C.
Analysis 50 C2,H2,N,C'204.C4H40, requires C, 53.01; H, 4.45; N, 7.42% 50 Found: C, 52.99; H 4.37; N, 7.66%.
Example 8
1,4-dihydro-2-[2-(1-imidazolyllethyl)-6-methyl-4(3-nitrophenyl)pyridine-3, 5 -dicarboxylic acid diethyl es 55 ter 55 1,4-Di hyd ro-6-m ethyl-2-(2-cl i methyl am i noethyl)-4-(3-n itro phenyl) pyridi ne-3,5-dica rboxyl ic acid diethyl ester (1.72g, 4mmol, prepared by analogy with Example 2(a)), methyl iodide (1 mi) and methanol (20mi) were refluxed for 1 hour, then evaporated to give a glass.
This was dissolved in chlorbenzene (20mi) and imidazole (2.179, 32 mmol) was added. The mixture was 60 refluxed for 13 hours and cooled to room temperature overnight, then washed three times with water, 60 dried and evaporated to give a solid, 0.68g. The sample was suspended in boiling methanol (5mi) and ethanolic HCl was added to give an acidic solution. This was cooled in ice and diluted with ether (15mi).
The resulting precipitate was triturated in ice, collected and dried (0. 82) to give the title compound as the HCl, 1/4H,0 salt, mp 174-WC.
10 GB 2 168 969 A 10 Analysis C,,H,,,N,O,,.HCl.114H,0 requires: C,55.76; H, 5.60; N, 11.31% Found: C, 55.96; H, 5.50; N, 10.98%.
Example 9 5
1,4-Dihydro-2-(1-imidazolylmethyl)-6-methyl-4-(3-nitrophenytipyridine-3,5di carboxylic acid diethyl ester 3-Nitrobenzaldehyde (1.51g, 1Ommol), ethyl 3-aminocrotonate (1.349, 1Ommol), and ethyl 3-oxo-4-(l imidazoiyi)butanoate oxalate. (2.86g, 1OmmoO were heated together in absolute ethanol (50mi) for 30 minutes under nitrogen..880 ammonia (3mi, 43.5mmol) was added to the hot suspension, giving, after a further 1 hour at reflux, a clear solution which then deposited a solid. After 5 hours at reflux the mixture 10 was allowed to cool overnight under N2 with exclusion of light.
The precipitate was removed and discarded, and filtrate was evaporated to give an oil, which was par titioned between ether (25mi) and 2N hydrochloric acid (10m1). The acid phase was extracted with further ether (2 x 15 mi), and the combined ether phases were washed with water (10mi) and discarded. The acid phase and the water wash were combined and extracted with chloroform (3 x 20mi). The CHCl., 15 extracts were combined, dried (Na,SOJ and evaporated to give a foam (1. 99g). This was crystallised from ethyl acetate (30 mi) to give the title compound (1.2g) mp 137-1400. This material was treated with ethan olic I-IC1 and recrystallised from ethyl acetate-ethanol to give the HCLI- 1,0 salt (0.84g), mp 132-70.
20 Analysis 20 C22H,,N,O,.HCl.H,.0 requires C, 53.4; H, 5.5; N, 11.3% Found: C, 53.8; H, 5.4; N, 11.1 Examples 10-14 25 By the general procedure described in Example 1 using reactants according to the following reaction 25 scheme 30 R 12 R 1 1 R 12 R 11 30 R'.,0'2 R 2 2 02 R10,C CO R 35 13 35 R i" \ 13 N X3 NH X3N R N R 2 U-_ I \---i 1 1 R R 40 40 the following compounds of formula ia are prepared:
Ex No. R R, R2 R11112 R13 -X3- M.P.CC) 45 45 10 H -(CH,),CN Et H,2-NO, Me -CH2 11 H -,Bu Et H,3-NO, Me -CH2 150-156 (HCl hemi hydrate) 12 H Me Et H,2-Cl Me -CH2- 190 c 50 13 H iPr Et H,3-NO, Me -CH:j- 11 5-117'(I-IC1, 50 ethanolate salt) 14 H Me Et 2,3-diCl Me -CH, 15 H Et Et H,3-NO2 EtOP -CH2 16 H Me Et H,3-NO2 EtO,CCH,- -CHr 55 55 Example 17-20
The compounds of Examples 10 and 11 are hydrolysed under basic conditions (using aqueous 1,2-di methoxy-methane) or acidic conditions respectively to give 60 Example 17: 1,4-dihydro-2-(imidazol-l-yiemthyi)-6-methy]-4-(2nitrophenyl)pyridine-3, 5-dicarboxylic 60 acid 3-ethyl ester.
Example 18: 1,4-dihyd ro-2-(i midazo-1 -yi methyl)-6-methyi-4-(3-nitro phenyl) pyridi n e-3,5-dica rboxyl ic acid 3-ethyl ester.
11 GB 2 168 969 A The compounds of Example 15 and 16 are hydrolysed under basic conditions to give respectively:
Example 19: 1,4-dihydro-2-(1-imidazolyimethyi)-4-(3-nitro-phenyi)pyridine -3,5,6-tricarboxylic acid 3,5-diethyl ester.
Example 20:1,4-dihydro-3-carbethoxy-5-carbomethoxy-2-(1-imidazolyimethyi)-4-(3-nitr ophenyi)-pyri- 5 dine-6-acetic acid. 5 Example 21
The compound of Example 1 is treated with sodium hydride and ethyl chloroacetate to give: 1,4-dihycl ro-1 -ca rbethoxym ethyi-2-(i m idazo 11 -yi methyl)-6-methyi-4-(3-n itro phenyl) pyridi n e, 3,5-dicarboxyllc 3ethyl 5-methyl ester 10 Examples 22-32 Using a procedure analogous to Example 9 and according to the reaction scheme.
15 ilo 2 C02 Et R 1 0 c Ar Et 15 C) L Ar- ref lux 2 C02 CHO ethanol NH + N B 2 0 B N N 20 H 20 the following compounds of formula 1 are prepared Ex,No. Ar RI 8 M.P.'C 25 25 22. 3-nitrophenyi Et NH2 174-5 (maleate) 23. pentafluoro- Me Me 200-208 (HCl) phenyl 24. 2-trifluoro- Me Me 165-8 Isuccinate) 30 methylphenyl 30 25. 3-methyithien-2-yi Me Me 155-159 (succinate) 26. quinol-4-yl Me Me 153-156 (diHCl,H20 salt) 35 27. benzofurazan-4-yi Me Me 186.5-190 (HCl) 35 28. 3-nitrophenyl N-CH2CH2- Me lz::/ 40 29. naphth-l-yl Me Me 40 30 2-(difluoro- Me Me methoxy)phenyl 31 3-cyanophenyi Me Me 32 2-methoxy- Me Me 45 phenyl 45 Example 33
1,4-Dihydro-2-(imidazol-l-ylmethyl)-6-methyl-4-(3-nitro-phenyl)pyridine-3, 5-d icarboxylic acid 3-(2-meth oxy)ethyl 5-methyl ester 50 A mixture of methyl 2-(3-nitrobenzyiidene)-acetoacetate (2.5g, 0.01 mol), ethanol (20 mi) and 2-methox- 50 yethyl 3-amino-4-(imidazol-l-yi)crotonate (39) is heated at reflux for 5 hours to give the title compound.
Example 34
4-(2,3-Dichlorophenyl)- 1,4-dihydro-2-(1-imidazolyl-methyl)-6methylpyridine-3,5-dicarboxylic acid, di methyl ester 55 Pyridinium perbromide hydrobromide (5.6g, 17.5 mmol) was added to a stirred ice-cooled solution of 4-(2,3-cl ich lo ro ph enyi)-1,4-di hyd ro-2,6-di methyl pyrid ine-3,5-d ica rboxyl ic acid dimethylester (5.55g, 15 mmol) and pyridine (2g) in methylene dichloride (80mi). The solution was stirred at ice temperature for minutes then washed with ice cold water ( 1 x 100 mi). The organic phase was separated and imida zole (6.8g, 0.1 mol) added followed by anhydrous Na,.SO, After drying for 20 minutes the solution was 60 filtered to remove NaSO4, evaporated and the residue heated on a steam bath for 40 minutes. The resi due was then dissolved in EtOAc, washed with water (2 x 50 mi), dried, evaporated and crystallised from methyl acetate (15 m]) to give the crystalline title compound (3.34g). This was suspended in isopropyl alcohol/methyl acetate (2:3v/v)and acidified with ethanolic HCl to give the hydrochloride salt on cooling, m.p. 167-1700C. 65 12 GB 2 168 969 A Analysis C2,H,^C1,0,MC1 0.5 H,0 requires: C,49.86; H, 4.39; N,832% Found: C, 49.98; H, 4.34; N, 8.54%.
Example 35
1,4-Dihydro-2-(l-imidazolylmethyl)-6-methyl-4-(3-nitro-phenyl)pyridine-3, 5-d icarboxylic acid dimethyl ester In a manner analogous to Example 34 1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylic acid 3,5 dimethyl ester was reacted with pyridinium perbromide hydrobromide and then imidazole to 10 give the title compound, m.p. 223-224'C (hydrochloride salt).
Analysis C,,H2,H,O,.HC I requires: C,53.51; H,432, NJ2.48% Found: C, 53.66; H, 4. 95; N, 12.48%.
Claims (29)
1. A compound of formula 20 R 1 0 Ar R 2 20 2C C02 B nMN 25 1 25 R or a salt thereof; wherein:
Ar is an optionally substituted aryl radical; R represents hydrogen or an optionally substituted alkyl or aralkyl group; R1 and R2 are the same or different and are selected from hydrogen and saturated or unsaturated, CYCHG or acyclic aliphatic hydrocarbon residues optionally substituted by one or more groups selected from halogen, OH, carboxy, CN, alkoxy, alkylthio, aryloxy, alkoxycar 35 bonyl, amino, substituted amino, and optionally substituted aryl; A represents a group of formula -XR3 35 wherein X is a group of formula -(CHR6),-Y-(CHR7).
or -(CHR6),-O-(CHR7)(CHs)r (i) in which formulae: Y represents -S-, NRI, or a direct bond, p and q each represent 0, 1 or 2 providing that p and q do not both represent zero when Y is a direct bond; one of r and s represents 0, 1 or 2 and the other is zero; RG, R7 and Ra independently represent hydrogen or lower alky], and R3 is an optionally sub stituted nitrogen ring heteroaryl radical optionally containing other ring heteroatoms selected from oxy gen, nitrogen or sulphur; and B represents hydrogen, carboxyl, lower alkoxycarbonyi, lower alkyl optionally substituted by amino, lower alkoxy, lower alkoxycarbonyl or carboxy], or amino optionally substituted by one or two lower alkyl groups.
2. A compound as claimed in Claim 1 in which R3 represesits a mono- or bicyclic nitrogen ring heter oaryl radical containing 5 to 10 ring atoms.
50
3. A compound as claimed in Claim 2 in which R3 is imidazolyl, pyridyl, thiazolyl, pyrrolyl, benzimida- 50 zolyl, quinoiyl, isoquinolyl or imidazopyridyl.
4. A compound as claimed in any one of Claims 1 to 3 wherein X represents -NH-, -0, -S-, -CH2-1 - CH(CH3)-, -CH(CHACH,-, -CH2CH(CH.,)-, OOCH2-, -CH,O-, -(CH2)2-0-, or a group of formula -CH2-Z-CH2-, - (CHJJ-CH2 or C1-12-Z_(CH1-where Z is -S-, -NH- or a direct bond.
5. A compound as claimed in any one of Claims 1 to 4 wherein Ar is optionally substituted phenyl, 55 pyridyl, quinolyl or benzimidazolyl.
6. A compound as claimed in Claim 5 wherein Ar is 2- or 3-nitrophenyl, 2, 3-dichlorophenyl, 2-trifluo romethylpheny], pentafl uo rom ethyl, pentaf 1 u oro phenyl, naphthy], pyridyl or halopyridyl.
7. A compound as claimed in any one of Claims 1 to 6 wherein B is H, CH3i-NH,-, NMe,-, NI-IMe-, NH2CH2-,CH,CH2-, CH3OCH2-,CH3OOC-,CH30OCCH,-, HOOC or HOOCCH,-.
8. A compound as claimed in any one of Claims 1 to 7 wherein R is hydrogen, methyl, ethyl, n-propy], isopropyl, benzyi, carbetfloxymethyl or carbmethoxy-methyi.
9. A compound as claimed in any one of Claims 1 to 8 wherein R, and/or R2 represent hydrogen or saturated or unsaturated acyclic hydrocarbon chains of 1 to 6 carbon atoms optionally substituted by aryl having 5 to
10 ring atoms, lower alkoxy, amino, diloweralkylamino, carboxy or loweralkoxycarbonyl. 65 13 GB 2 168 969 A 13 10. A compound as claimed in any one of Claims 1 to 9 wherein R1 and/or R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, methoxymethyl, ethoxymethyl, methoxy propyl, aminomethyl, 2-aminoe thy[, 3-aminopropyl, dimethylaminoethyl, 2-carboxyethyl, meth oxyca rbo nyl m ethyl, ethoxycarbonylme thyl, pyridylmethyl, pyridylethyl, imidazolylmethyl or imidazolylethyl.
5
11. 1,4-Dihydro-2-(imidazol-1-ylmethyl)-6-methyl-4-(3nitrophenyl)pyridine-3,5-d icarboxylic acid 3-ethyl 5 5-methyl diester or a pharmaceutically acceptable salt thereof.
12. 1,4-Dihydro-2-[2-(imidazol-1-yl)-ethy[J-6-methyl-4-(2nitrophenyl)pyridine-3,5-dicarboxylic acid die thyl ester or a pharmaceutically acceptable salt thereof.
13. 1,4-Dihydro-2-[2-(l-imidazolyl)ethyll-6-methyl-4-(2nitrophenyl)pyridine-3,5 -dicarboxylic acid di- methyl ester or a pharmaceutically acceptable salt thereof. 10
14. 1,4-Dihydro-2-methyl-4-(3-nitrophenyl)-6-[(3pyridyloxy)methyllpyridine-3,5-d icarboxylic acid 5ethyl-3-methyl diester or a pharmaceutically acceptable salt thereof.
15. 2-[2-0 -Be nzi m idazolyl [)ethyl]-4-[2,3-d ich I o ro-p henyll-1,4di hydro-6-methyl pyrid i ne-3,5-dica rboxyl ic acid dimethylester or a pharmaceutically acceptable salt thereof.
15
16. 4-(2,3-Dich I o roph enyl)- 1,4-d i hyd ro-2-m ethyl-6-(2-[2methyl (1 A m idazo lyl)] ethyl) pyrid ine-3,5-d ica r- 15 boxylic acid, dimethyl ester or a pharmaceutically acceptable salt thereof.
17. 4-(2,3-D ich I o ro ph enyl)- 1,4-d! hyd ro-2-[2-(l -i m idazolyl)ethyl 1-6-m ethyl pyrid i ne-3,5-dica rboxyl ic acid, dimethyl ester or a pharmaceutically acceptable salt thereof.
18. 1,4-Dihydro-2-[2-(l-imidazolyl)1-6-methyl-4-(3-nitrophenyl)pyridine-3, 5-dica rboxylic acid diethyl es- 20 ter or a pharmaceutically acceptable salt thereof. 20
19. 1,4-Dihydro-2-(l-imidazolylmethyl)-6-methyl-4-(3-nitrophenyl)pyridine3,5-di carboxylic acid diethyl ester or a pharmaceutically acceptable salt thereof.
20. 1,4-Dihydro-2-(imidazol-1-ylmethyl)-6-methyl-4-(3nitrophenyl)pyridine-3,5-d icarboxylic acid 3-ethyl 5-isopropyl diester or a pharmaceutically acceptable salt thereof.
25
21. 1,4-Di hyd ro-2-(i m idazo 1 -1 -yl methyl)-6-m ethyl -4-(quinol-4yl)pyridine-3,5-dicarboxylic acid 3-ethyl 5- 25 methyl diester or a pharmaceutically acceptable salt thereof.
22. A compound as claimed in any one of Claims 1 to 21 when in the form of a salt with an acid selected from hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, malonic, formic, maleic, methanesulphonic or p-toluenesulphonic.
30
23. A process for preparing a compound of formula I as claimed in Claim 1 which comprises one of 30 the following:
(i) reacting compounds of formulae 11, 111 and IV:
Ar 35 R 1 0 2 C 1-1 Co 2 R 2 35 RNH 2 and 40 T 0 0 T 2 40 (II) (III) (IV) in which formulae Ar, R, Ri and R2 are as defined in Claim 1 and one of T, and T2 is A, the other is B wherein A as defined in Claim 1 and B is H, lower alkoxycarbonyl, carboxyl or optionally substituted 45 lower alkyl, providing that a) r cannot be zero, b) when Y is -S- or -NR8- then p is 1 or 2 to give a corresponding compound of formula 1; or (ii) reacting a compound of formula (11) R 1 0 2 C Ar (II) T 1 0 with a compound of formula (V) CO 2 R 2 ic 2 M RHN T 14 GB 2 168 969 A 14 in which formulae Ar, R, R, and R2 are as defined in Claim 1 and one of TI and T2 is A, the other is B wherein A and B are as defined in Claim 1 providing that when T2 is A then TI is other than optionally substituted amino and further providing that a) r cannot be zero and 5 b) when Y is -S- or -NRa- then p is 1 or 2, to give a corresponding compound of formula 1; or (iii) reacting a compound of formula ArCHO 10 10 with compounds of formulae V and Vi R' 02C C02 R is T 11 0 and RNH 1 T 2 15 (VI) (V) 20 20 in which formulae Ar, R, R' and R2 are as defined above and one of TI and T2 is A, the other B wherein A and B are as defined in Claim 1 providing that when T2 is A, TI cannot be optionally substituted amino and further providing that a) r cannot be zero and b) when Y is -S- or - NRII- then p is 1 or 2, to give a corresponding compound of formula 1, or (R) reacting a compound of formula V11 - Ar R 102 c C01)R 2 6 1 30 13 D 1 II(CM M (VII) 30 with a compound of formula Vill 35 Z2(CHR7),R3 (V111) 35 in which formulae B, R, W, R2, R3, R6 and R7 are as defined in Claim 1; one of ZI and Z2 is halogen or a sulphonyloxy group, the other of ZI and Z2 is -YH, -Y-, -OH or -0- as appropriate wherein Y is as defined in Claim 1; and v and w are each independently 0, 1 or 2 with the provisos that 40 (a) when v is 2 and Z2 is YH or YE) then ZI can also represent dialkylamino or a quaternary ammonium 40 group,and (b) when one of ZI and Z2 is -OH or -0(3 then one of v and w is 0; or (v) alkylating in the presence of a strong base a compound of formula 1 as defined in Claim 1 wherein 45 R is hydrogen with an alkylating agent of formula 45 R - Z:1 where R is as defined in Claim 1 except hydrogen and Z3 is halogen or a sulphonyloxy group to give a corresponding compound of formula 1, 50 or (vi) hydrolysing selectively if desired a compound of formula 1 as defined in Claim 1 having an ester group to give a compound of formula 1 having a carboxyl group, or 55 (vii) esterifying a compound of formula 1 as defined in Claim 1 having a carboxy group to give a corn- 55 pound of formula 1 as defined in Claim 1 having an ester group, or (viii) reacting a compound of formula 1 as defined in Claim 1 having a carboxyl group with a base to form a salt thereof or acidifying a salt carboxylate of a compound of formula 1 to give the free acid, or 60 (ix) converting a compound of formula 1 as defined in Claim 1 to an acid addition salt thereof by addi tion of acid or basifying an acid addition salt to give a compound of formula 1, or (x) converting a compound of formula 1 as defined in Claim 1 having basic substituent to a quaternary ammonium salt thereof by reaction with an alkylating agent. 65 15 GB 2 168 969 A 15
24. A process as claimed in Claim 23 for preparing a compound of formula I substantially as her einbefore described with reference to any one of Examples 1, 2(b) and 3 to 35.
25. A compound of formula I as claimed in Claim 1 whenever prepared by a process as claimed in Claim 23 or Claim 24.
5
26. A compound of formula I as claimed in any one of Claims 1 to 22 for use as a pharmaceutical. 5
27. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 1 to 22 and a pharmaceutically acceptable carrier.
28. Use of a compound of formula I as claimed in any one of Claims 1 to 22 for the manufacture of a medicament for the treatment or prevention of cardiovascular disorders.
10
29. Use of a compound of formula I as claimed in any one of Claims 1 to 22 for the manufacture of a 10 medicament for the treatment or prevention of thrombosis.
Printed in the UK for HMSO, D8818935, 5/86, 7102.
Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848421039A GB8421039D0 (en) | 1984-08-17 | 1984-08-17 | Heterocyclic compounds |
| GB858515751A GB8515751D0 (en) | 1985-06-21 | 1985-06-21 | Heterocyclic compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8520485D0 GB8520485D0 (en) | 1985-09-18 |
| GB2168969A true GB2168969A (en) | 1986-07-02 |
| GB2168969B GB2168969B (en) | 1987-09-03 |
Family
ID=26288137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08520485A Expired GB2168969B (en) | 1984-08-17 | 1985-08-15 | 1,4-dihydro pyridines |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5068337A (en) |
| EP (1) | EP0172029B1 (en) |
| JP (1) | JPH0680053B2 (en) |
| KR (1) | KR930000167B1 (en) |
| AR (1) | AR241417A1 (en) |
| AT (1) | ATE61055T1 (en) |
| AU (1) | AU587388B2 (en) |
| CA (1) | CA1310011C (en) |
| CZ (1) | CZ279473B6 (en) |
| DE (1) | DE3581858D1 (en) |
| DK (1) | DK374185A (en) |
| ES (1) | ES8604564A1 (en) |
| FI (1) | FI89166C (en) |
| GB (1) | GB2168969B (en) |
| GR (1) | GR851819B (en) |
| HU (1) | HU194868B (en) |
| IE (1) | IE58706B1 (en) |
| IL (1) | IL75943A (en) |
| MY (1) | MY101736A (en) |
| NZ (1) | NZ212956A (en) |
| PH (1) | PH26049A (en) |
| PT (1) | PT80956B (en) |
| SU (1) | SU1486059A3 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2211188A (en) * | 1987-12-17 | 1989-06-28 | Wyeth John & Brother Ltd | New crystal form |
| WO1999001432A1 (en) * | 1997-07-03 | 1999-01-14 | Latvias Organiskas Sintezes Instituts | Anti-diabetic agent |
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| CA1267416A (en) * | 1985-06-17 | 1990-04-03 | Ila Sircar | 1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders |
| IT1204421B (en) * | 1986-06-27 | 1989-03-01 | Boehringer Biochemia Srl | 2- (AMINOALKYLTIO) METHYL-1,4-DIHYDROPYRIDINE, A METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| EP0225175A3 (en) * | 1985-11-28 | 1988-12-28 | FISONS plc | Dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions thereof |
| GB8602518D0 (en) * | 1986-02-01 | 1986-03-05 | Wyeth John & Brother Ltd | 1 4-dihydropyridines |
| DE3617976A1 (en) * | 1986-05-28 | 1988-01-14 | Alter Sa | 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN ANTITHROMBOTIC MEDICATIONS |
| FR2602231B1 (en) * | 1986-08-04 | 1988-10-28 | Adir | NOVEL 1,4-DIHYDRO PYRIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| JPH02501736A (en) * | 1986-12-24 | 1990-06-14 | ベリンガー マンハイム イタリア エッセ ピ ア | Novel aralkyl-1,4-dihydropyridine and method for producing the same, and pharmaceutical compositions containing the same |
| JPH0286981A (en) * | 1988-09-22 | 1990-03-27 | Aisin Seiki Co Ltd | Rotary compressor |
| US5616591A (en) * | 1992-03-27 | 1997-04-01 | E.R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted quinoline derivatives |
| DE4233601A1 (en) * | 1992-10-06 | 1994-04-07 | Bayer Ag | 3-substituted quinoline-5-carboxylic acids |
| WO1995000649A1 (en) * | 1993-06-25 | 1995-01-05 | Smithkline Beecham Plc | Lipoprotein associated phospholipase a2, inhibitors thereof and use of the same in diagnosis and therapy |
| EP1309555B1 (en) * | 2000-12-29 | 2005-07-27 | Pfizer Limited | Process for making amlodipine maleate |
| DE60236851D1 (en) * | 2001-02-14 | 2010-08-12 | Warner Lambert Co | Pyrimidinmatrixmetalloproteinaseinhibitoren |
| US6566359B1 (en) | 2002-05-20 | 2003-05-20 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | 2,4,6-trimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid esters as neuroprotective drugs |
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| EP0100189A2 (en) * | 1982-07-22 | 1984-02-08 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents |
| US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
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| GB1552911A (en) * | 1975-07-02 | 1979-09-19 | Fujisawa Pharmaceutical Co | 1,4 dihydropyridine derivatives and the preparation thereof |
| DE2639257A1 (en) * | 1976-09-01 | 1978-03-02 | Bayer Ag | AMINOALKYLIDENAMINO-1,4-DIHYDROPYRIDINE, PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| DE2658183A1 (en) * | 1976-12-22 | 1978-07-06 | Bayer Ag | 2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT |
| US4177278A (en) * | 1977-04-05 | 1979-12-04 | Bayer Aktiengesellschaft | 2-Alkyleneaminodihydropyridines compounds, their production and their medicinal use |
| DE2738153A1 (en) * | 1977-08-24 | 1979-03-08 | Bayer Ag | 2-PYRIDYL-1,4-DIHYDROPYRIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| US4307103A (en) * | 1978-09-08 | 1981-12-22 | Fujisawa Pharmaceutical Co., Ltd. | Dihydropyridine derivative, processes for preparation thereof and pharmaceutical composition comprising the same |
| JPS5547656A (en) * | 1978-09-29 | 1980-04-04 | Dainippon Pharmaceut Co Ltd | 2-(2-substituted aminoethyl)-1,4-dihydropyridine derivative and its derivative |
| DE2844595A1 (en) * | 1978-10-13 | 1980-04-30 | Bayer Ag | 2-Acylamino:alkyl-di:hydro-pyridine derivs. - useful as cardiovascular agents acting as coronary dilators, hypotensives, antiarrhythmics, vascular spasmolytics and hypolipaemics |
| CS228917B2 (en) * | 1981-03-14 | 1984-05-14 | Pfizer | Method of preparing substituted derivatives of 1,4-dihydropyridine |
| SE8105230L (en) * | 1981-09-03 | 1983-03-04 | Haessle Ab | NEW DIHYDROPYRIDINES |
| DE3269219D1 (en) * | 1981-11-17 | 1986-03-27 | Fisons Plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| DE3207982A1 (en) * | 1982-03-05 | 1983-09-08 | Bayer Ag, 5090 Leverkusen | NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS |
| DK161312C (en) * | 1982-03-11 | 1991-12-09 | Pfizer | CHANGES FOR THE PREPARATION FOR THE PREPARATION OF 2-Amino-CO-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-2-D-Hydroxy |
| WO1983003249A1 (en) * | 1982-03-17 | 1983-09-29 | Yoshitomi Pharmaceutical | 1,4-dihydropyridine-3,5-dicarboxylate derivatives |
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- 1985-07-23 GR GR851819A patent/GR851819B/el unknown
- 1985-07-24 IE IE186085A patent/IE58706B1/en not_active IP Right Cessation
- 1985-07-26 AR AR85301104A patent/AR241417A1/en active
- 1985-07-29 IL IL75943A patent/IL75943A/en not_active IP Right Cessation
- 1985-07-31 CA CA000487896A patent/CA1310011C/en not_active Expired - Fee Related
- 1985-08-01 NZ NZ212956A patent/NZ212956A/en unknown
- 1985-08-02 AU AU45726/85A patent/AU587388B2/en not_active Ceased
- 1985-08-13 FI FI853103A patent/FI89166C/en not_active IP Right Cessation
- 1985-08-14 PT PT80956A patent/PT80956B/en not_active IP Right Cessation
- 1985-08-14 PH PH32635A patent/PH26049A/en unknown
- 1985-08-15 DE DE8585305803T patent/DE3581858D1/en not_active Expired - Fee Related
- 1985-08-15 AT AT85305803T patent/ATE61055T1/en not_active IP Right Cessation
- 1985-08-15 EP EP85305803A patent/EP0172029B1/en not_active Expired - Lifetime
- 1985-08-15 GB GB08520485A patent/GB2168969B/en not_active Expired
- 1985-08-15 CZ CS855922A patent/CZ279473B6/en unknown
- 1985-08-16 KR KR1019850005902A patent/KR930000167B1/en not_active IP Right Cessation
- 1985-08-16 JP JP60180894A patent/JPH0680053B2/en not_active Expired - Lifetime
- 1985-08-16 HU HU853175A patent/HU194868B/en not_active IP Right Cessation
- 1985-08-16 SU SU853940051A patent/SU1486059A3/en active
- 1985-08-16 DK DK374185A patent/DK374185A/en unknown
- 1985-08-16 ES ES546189A patent/ES8604564A1/en not_active Expired
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- 1986-11-13 US US06/930,972 patent/US5068337A/en not_active Expired - Fee Related
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| EP0100189A2 (en) * | 1982-07-22 | 1984-02-08 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents |
| US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2211188A (en) * | 1987-12-17 | 1989-06-28 | Wyeth John & Brother Ltd | New crystal form |
| US4983617A (en) * | 1987-12-17 | 1991-01-08 | John Wyeth And Brothers Limited | Stable crystal form of 1,4-dihydro-2-(imidazolyl-1-ylmethyl)-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester, hydrochloride |
| GB2211188B (en) * | 1987-12-17 | 1991-08-21 | Wyeth John & Brother Ltd | New crystal form |
| WO1999001432A1 (en) * | 1997-07-03 | 1999-01-14 | Latvias Organiskas Sintezes Instituts | Anti-diabetic agent |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19990815 |