AU621667B2 – Sulphonamido-phenylalkanoic acid derivatives having thromboxane A2 antagonist activity
– Google Patents
AU621667B2 – Sulphonamido-phenylalkanoic acid derivatives having thromboxane A2 antagonist activity
– Google Patents
Sulphonamido-phenylalkanoic acid derivatives having thromboxane A2 antagonist activity
Download PDF
Info
Publication number
AU621667B2
AU621667B2
AU42578/89A
AU4257889A
AU621667B2
AU 621667 B2
AU621667 B2
AU 621667B2
AU 42578/89 A
AU42578/89 A
AU 42578/89A
AU 4257889 A
AU4257889 A
AU 4257889A
AU 621667 B2
AU621667 B2
AU 621667B2
Authority
AU
Australia
Prior art keywords
phenyl
compound
butyric acid
formula
dimethyl
Prior art date
1988-10-10
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU42578/89A
Other versions
AU4257889A
(en
Inventor
David Gwyn Cooper
Andrew Derrick Gribble
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1988-10-10
Filing date
1989-10-05
Publication date
1992-03-19
1989-10-05
Application filed by Smith Kline and French Laboratories Ltd
filed
Critical
Smith Kline and French Laboratories Ltd
1990-04-12
Publication of AU4257889A
publication
Critical
patent/AU4257889A/en
1992-03-19
Application granted
granted
Critical
1992-03-19
Publication of AU621667B2
publication
Critical
patent/AU621667B2/en
2009-10-05
Anticipated expiration
legal-status
Critical
Status
Ceased
legal-status
Critical
Current
Links
Espacenet
Global Dossier
Discuss
Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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
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
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
A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
Abstract
Compounds of the formula (I):
Description
COMMONWEA4LTH OF AUSTRAUA PATENTS ACT 19 NAME ADDRESS OF APPLICANT: Smith Kline French Laboratories Limited Mundells Weiwyn Garden City Hertfordshire AL7 IEY United Kingdom NAME(S) OF INVENTOR(S): David Gwyn COOPER a: Andrew Denrick GRIIBBLE ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melboturnt, 3000.
a a ~COMPLETE SPECIFICATi.» FOR THE RiVENTION ENITLED Suiphonamido phenykhklanoic acid derivatives having thromboxane A2 a antagonist activity The following statement is a full description of this invention, including the best method of performing it known to me/us:-
RA
‘I
-la- The present invention relates to a class of phenylalkanoic acid compounds containing a sulphonamido group which have activity as thromboxane
A
2 antagonists, to the use of the compounds in medicine, to pharmaceutical compositions containing them and to methods for their preparation.
0* 10 o0 o 15 o 15 9 *20 r 25 25 Thromboxane A 2
(TXA
2 is a potent vasoconstricting and platelet aggregating agent which is formed in platelets and other tissues as a product of the «arachidonic acid cascade». TXA 2 is produced by the thromboxane synthetase catalysed conversion of prostaglandin H 2
(PGH
2 which in turn is produced, via the intermediacy of prostaglandin G 2
(PGG
2 by the action of cyclooxygenase on arachidonic acid. The potency of TXA 2 is such that very small amounts can trigger serious biological consequences and it has been implicated in mediating pathophysiological actions in severe disorders such as circulatory shock and myocardial ischaemia.
One method of inhibiting the effects of thromboxane
A
2 is through the selective antagonism of TXA 2
/PGH
2 at the receptor level and various compounds have been reported as TXA 2 receptor antagonists, see for example U.S. 4,536,510 and U.S. 4,443,477.
The present invention provides a compound of the formula R1-SONH- 2A-COH -CO H and salts thereof, wherein R 1 is phenyl optionally substituted by one or more substituents chosen from halogen, Cl-4alkyl, Cl-6acyl, Cl_4alkoxy, nitro and trifluoromethyl; and A is an acyclic hydrocarbon group having from 2 to 8 linear carbon atoms, provided that when A is CH=CH, ;CH 2 2 or (CH 2 3
R
1 is other than 4phenyl methyl.
A is preferably an acyclic hydrocarbon group having from 2 to 6 linear carbon atoms, more preferably 2 to 4 linear carbon atoms.
By linear carbon atoms is meant those carbon atoms extending in an unbranched chain between the phenylene ring and the carboxyl group. Each linear carbon atom can be substituted by one or two C 1 _2alkyl substituents, preferably methyl substituents. It is preferred that the total number of carbon atoms in the group A does not i: exceed Particular group A are (CH 2 3
(CH
2 4
(CH
2 2
C(CH
3 2 and (CH 2 3
C(CH
3 2 a preferred group being (CH 2 )3.
R
1 is suitably an unsubstituted phenyl group or, 25 more suitably a phenyl group substituted by one or two S» substituents, preferably one of which is located at the 4-position of the phenyl ring.
Particular substituents are bromine, chlorine, methyl, methoxy, trifluoromethyl and nitro, particularly preferred substituents being bromine and chlorine.
Preferred groups R 1 include 4-chlorophenyl and 4bromophenyl.
The group A-CO 2 H can be ortho, meta or para with respect to the group R 1
SO
2 NH but particularly it is in the para position.
920110,dabcmc.001,42578-89.res,2 r 11981 -3- Preferred compounds of eLLe present invention are 4-[4-(phenylsulphonamido)phonflJbutyric acid; 4 -[4-(4-chlorophenylsulphonamido)phenyl]butyric acid; 4-(4-(4-bromophenylsulphonamido)phenyl]butyric acid; A4r -I (A mttnynlclh 3.iop1cl~-i- oi 4-[4-(4-methoxyphenylsulphonamido)phenyl]butyric acid; 2,2-dimethyl-4-[4-(4-methylphenylsulphonamido)phenyl]butyric acid; 2,2-dimethyl-4-[4-(4-chlorophenylsulphonamido)phenyl]bcyric acid; 2 2 -dimethyl-4-[4-(4-bromophenylsulphonamido)phenyl]butyric acid; 2, 2 -dinethyl-4-[4-phenrylsulphonamido)phenyl]butyric acid; srt and 2, 2-dimethyl-4-[4-(4-mrethoxyphenylsulphonamido)phenyl] butyric acid; and pharmaceutically acceptable salts thereof.
Compounds of the formula can form carboxylate salts and salts of the sulphonamide group.
Examples of carboxylate salts are alkali metal, alkaline earth metal and ammonium salts. Alkali and t talkaline earth metal salts typically are formed by interaction of a carboxylic acid with a metal alkoxide or hydroxide whereas ammonium salts typically are formed by interaction of the carboxylic acid with the appropriate amine or the appropriate ammonium hydroxide.
It is preferred that the salts are pharmaceutically acceptable, although non-pharmaceutical salts are also within the scope of the invention. Such salts can be converted into pharmaceutically acceptable salts or into the corresponding free base or free acid.
i’-I Ila 11981 -4- Where the compounds of formula exist as solvates, for example hydrates and alcoholates, such forms are also within the scope of the invention.
Compounds of the formula can be prepared by the reaction of a compound of the formula (II):
H
2 N- (II) A-CO2H or a carboxylate salt, amide or ester thereof, with a compound R 1
SO
2 L where L is a leaving group displaceable by amino.
o os o oo 15 Examples of leaving groups L are the halogens, S. particularly chlorine.
o@ o o The reaction of compounds of the formula (II) with compounds of the formula R 1 S0 2 L can be conducted under conditions known for the preparation of analogous sulphonamides. Thus, for example, the reaction can be conducted in a solvent, for oxample benzene, toluene or a polar solvent such as acetone, acetonitrile, a S0 halogenated hydrocarbon such as dichloromethane or a basic solvent such as pyridine, with heating where required, for example at the reflux temperature of the solvent. Where the solvent is non-basic the reaction typically is conducted in the presence of a base such as S pyridine or a trialkylamine such as triethylamine.
Alternatively, the reaction can be conducted under Schotten-Baumann conditions, i.e. the reactants are stirred or shaken together in the presence of an aqueous alkali such as dilute sodium hydroxide.
Compounds of the formula (II) can be prepared from a compound of the formula (III): 02N O2N/ (III)
A-CO
2
H
by treatment with an appropriate reducing agent, for example by hydrogenating over a transition metal catalyst such as palladium on charcoal, or by treatment with hydrazine in the presence of palladium on charcoal.
Suitable solvents for use in such reactions are Cl_ 4 alkanols such as methanol and ethanol and typically the reaction is conducted at approximately ambient temperature.
Some of the compounds of the formula are useful in the treatment of diseases in which TXA 2 is a factor.
Thus they are also useful in the treatment of disorders in which aggregation of blood platelets and vasoconstriction play a part.
In a further aspect, therefore, the present invention provides a method for the treatment of a thromboxane-A 2 mediated disease which comprises administering to a patient in need of su.ch treatment a therapeutically effective amount of a compound of the formula (IB):
R-SO
2 NH (IB)
A-CO
2
H
and salts thereof, wherein R 1 is phenyl optionally substituted by one or more substituents chosen from halogen, C 1 -4alkyl, C 1 -6 acyl, C 1 4 alkoxy, nitro and fi trifluoromethyl; and A is an acyclic hydrocarbon group l having from 2 to 4 linear carbon atoms.
S911009,dbdat085,42578.res,5 r.
Li -1 5a Particular clinical indications in which the compounds of the formula (IB) would be of interest include the treatment or management of post myocardial infarction, coronary thromboses in combination with tissue plasminogen activator and other thrombolytics), unstable angina, transient ischaemia, coronary artery bypass grafts, cardiac valve replacements and peripheral and vascular grafts including for example renal transplants.
The compounds of the formula (IB) can be administered as the pure compound but it is more usual to administer them as part of a pharmaceutical composition in association with a carrier and one or more excipients.
r ~1 t
O
r
L
r rr r r r r «~i
(I
0 r rr
I
911009,dbdat85,42578.res,6 -L _i-L i a 44 0a 00 9 04 11981 -6- In a further aspect, therefore, the present invention provides a pharmaceutical composition comprising a compound of the formula(\B) and a pharmaceutically acceptable carrier.
The compositions can be administered in standard manner, for example orally, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula (\)and their pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, starch, lactose and sucrose.
Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil. Such compositions can be administered, for example, by bolus injection or by infusion.
S0 *e 0 6 0 00 0 9e 0t
A
1 11981 -7- A typical suppository formulation comprises a compound of formula or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
00 0 0 0 00 00 0, Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be S. 15 administered in the form of an aerosol using a S conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
Preferably the composition is in unit dosage form, 20 for example a tablet, capsule or metered aerosol dose, so Sthat the patient may administer to himself a single dose.
*ao, Each such dosage unit suitably contains from 1 mg to oo 0 1 g, preferably from 5 mg to 500 mg, e.g. 100 mg or 200 o o 25 mg, of a compound of the formula(le) or a pharmaceutically .o acceptable salt thereof calculated as the compound itself.
o A typical daily dosage regimen is 10 mg to 1 g for an average human weighing approximately 70 kg, administered in 1 to 4 dosage units, preferably 1 or 2.
The compositions of this invention, in addition to containing a compound of the formula can also contain other agents; for example one or more agents chosen from phosphodiesterase inhibitors, hypolipidaemic agents, platelet aggregation inhibitors, vasodilators, RA ‘A c0 JU 11981 -8- B-adrenergic receptor blockers, ACE inhibitors, tissue plasminogen activator and other thrombolytics, and antiarrhythmics.
The compositions of the present invention are prepared by bringing the active constituent into association with a pharmaceutically acceptable carrier and optionally other excipients and ingredients as defined above.
As indicated above, compounds of the formula (Is) have biological activity that is indicative of an ability 0Ooo to antagonise TXA 2 receptors. The TXA 2 activity has been demonstrated in the human platelet binding assay.
.o o The platelet binding assay used was essentially the 0 method described by Mais et al, J. Pharm. Exp. Ther., 1985, 235(3), 729-734 where [1 25 I]PTA-OH was used as the receptor ligand.
The IC 5 0 values represent the concentration which o o0’ produces a 50% inhibition of specific 1 2 5
I]PTA-OH
binding.
;mo 25 The compounds of Examples 1 to 4 had IC 5 0 values Sin the range of 0.02 to 0.6 pM in the platelet binding D» assay.
The following Examples are illustrative of the invention.
In the Examples, all temperatures are in °C.
Melting points are uncorrected and were obtained in an open capillary tube using a BUchi 510 Melting Point Apparatus.
cg -ns~ I PI I L ~-3-C 11981 -9- Example 1 A. 4-(4-Aminophenyl)butyric acid 0 99 *s 00 0 04 9 99 0d 99 0 09 89r 04 9 9 9, 9t 9009 0 9 9 )i 0 A mixture of 4-(4-nitrophenyl)butyric acid (3g, 14mmol) (Aldrich Chemical Company Ltd.) and 10% palladium on charcoal catalyst (0.3g) in ethanol (100ml) was submitted to gaseous hydrogen at 50p.s.i., 20°C, for minutes. The mixture was then filtered and concentrated.
The resulting solid residue was recrystallised from isopropanol to give 4-(4-aminophenyl)butyric acid.
(1.9g, 76%) mp. 125-1270C.
B. 4-r4-(Phenylsulphonamido)phenyllbutyric acid To a solution of 4-(4-aminophenyl)butyric acid (1g, 5.6mmol) in dry acetone (30ml) was added dropwise a solution of benzenesulphonyl chloride (0.99g) and pyridine (l.ig) in dry acetone (10ml). The mixture was heated at reflux for 3 hours, then concentrated in vacuo. The resulting oil was dissolved in dichloromethane (100ml) and the solution was washed with 2N aqueous HC1 (2 x 100ml), followed by water (2 x 100ml). The dichloromethane solution was extracted with 25 10% aqueous NaOH (2 x 50ml), followed by water (2 x and these extracts were combined and stirred with dichloromethane (100ml) while conc. HC1 was added to adjust the pH of the mixture to 5. The layers were separated and the organic solution was dried (MgSO 4 and concentrated in vacuo. The resulting solid was recrystallised from isopropanol to give 4-[4-(phenylsulphonamido)phenyl]butyric acid. (1.03g, 58%) mp. 128-130aC.
Found: C 60.19 Requires: C 60.17
C
16
H
17
NO
4
S
H 5.47 N 4.31 H 5.37 N 4.39 S 10.00 S 10.04
I
1198 1 Examples 2 to 4 Using the method described in Example 1, the following compounds were -‘:prd In each case, the appropriate phenylsulphonyl chloride was obtained from a commercial source.
2. (4-Chlorophenylsulphonamido)phenyl]butyric acid; melting point 150-151 0
C.
Found: C 54.59 H 4.72 N 3.72 S 8.83 Cl 9.88 Requires: C 54.31 H 4.56 N 3.96 S 9.06 Cl 10.02 9, 4-114- (4-Methoxyphenylsulphonamido)phenyl]butyric 04 acid; melting point 176-177 0
C
Found: C 58.67 H 5.57 N 3.95 S 9.28 Requires: C 58.40 H 5.48 N 4.01 S 9.18 4. (4-Bromophenylsulphonamido)phenyl3butyric ac-id.
melting point 168-1690C 00aFound:. C 48.17 H 4.13 N 3.40 S 7.92 Br 20.33 *Requires: C 48.25 H 4.05 N 3.52 S 8.05 Br 20.06.
*too
Claims (8)
1. A compound of the formula R 1 -so0 NH (I) 2KIQ A-CO2H and salts thereof, wherein R 1 is phenyl optionally substituted by one or more substituents chosen from halogen, Cl. 4 alkyl, C 1 .acyl, Cl- 4 alkoxy, nitro and trifluoromethyl; and A is an acyclic hydrocarbon group having from 2 to 4 linear carbon atoms, provided that when A is (CH 2 2 or (CH 2 3 F
