IE914409A1

IE914409A1 - Anti-inflammatory compounds

Info

Publication number: IE914409A1
Application number: IE440991A
Authority: IE
Original assignee: Searle & Co
Priority date: 1990-12-19
Filing date: 1991-12-18
Publication date: 1992-07-01
Also published as: PT99833A; WO1992011252A1; AU9134991A

Abstract

This invention encompasses compounds of formula (I) and the stereoisomers and pharmaceutically acceptable salts thereof. In formula (I) R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH2)m-R<3> wherein R<3> represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; R1 is -CONH2 or alpha wherein R2 is lower alkyl, phenyl, unsubstituted or substituted with loweralkyl, or beta ; and n is an integer from 2 to 5. The compounds are useful anti-inflammatory agents for treating, for example, inflammatory bowel disease, rheumatoid arthritis, gout, asthma and psoriasis.

Description

ANTI-INFLAMMATORY COMPOUNDS Background of the Invention Leukotriene D4 and C4 (LTD4/LTC4) and leukotriene B4 (LTB4) are products of the arachidonic acid metabolic pathway. LTD4 and LTC4 are associated with smooth muscle contraction and contract guinea pig ileum, human and guinea pig bronchi and human pulmonary artery and vein. LTB4 is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB4 is believed to be an important mediator of inflammation. High levels of LTB4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB4 are useful in the therapy of such diseases.

Gastroenterology. 1985: 88 : 580-7 discusses the role of arachidonic acid metabolites in inflammatory bowel disease.

British Medical Bulletin. (1983), vol. 39, No. 3, pp. 249-254, generally discusses the pharmacology and pathophysiology of leukotriene B4.

Biochemical and Biophysical Research Communications, Vo1. 138, No. 2 (1986), pp. 540-546 discusses the pharmacology of a specific LTB4 antagonist which has a different structure than compounds of this invention.

The Journal of Medicinal Chemistry. 1977, Vol. 20 (3): 376 discloses a compound similar to the compounds of Formula I.

The prior art generally describes the above compounds /A 1169U.WPF as LTD4 antagonists for use as anti-allergy compounds or as antagonists of SRS-A, the slow reacting substance of anaphylaxis. In sharp contrast, compounds of Formula I are selective LTB4 antagonists useful in treating inflammatory diseases.

U.S. 4,281,008, U.S. 3,822,148, and U.S. 4,006,245 generically disclose formulae which encompass compounds similar to Formula I but do not exemplify or otherwise enable the preparation and use of such compounds, nor do they teach the selective LTB4 antagonist activity of compounds of the present invention.

U.S. 4,889,871 generically discloses formulae which encompass the compound 1 described in Scheme 1 herein and which is used as an intermediate in the preparation of the compounds of this invention. The compounds are disclosed as useful antiinflammatory agents. -2IE 914409 1169U.WPF Summary of the Invention This invention encompasses compounds of the following formula and the stereoisomers and pharmaceutically acceptable salts thereof. wherein R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH2)m-R3 wherein R3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; II Rj is -CONH2 or - C - NHSO2R2 wherein R2 is lower alkyl, phenyl, H unsubstituted or substituted with lower alkyl, or \ ; and n N—n is an integer from 2 to 5. / \\ -3IE 914409 1169U.WPF These compounds are selective antagonists of leukotriene B4 (LTB4) with little or no antagonism of leukotriene D4 (LTD4) and are useful anti-inflammatory agents for treating inflammatory bowel disease, rheumatoid arthritis, gout, asthma and psoriasis.

Detailed Description of the Invention This invention encompasses the compounds of Formula I as previously described.

Preferred embodiments of the present invention are compounds of the Formula Ia, and the stereoisomers and pharmaceutically acceptable salts thereof, R Ο Ia wherein R is propyl, 2-propenyl or cyclopropylmethyl, and Rx is II -c-nhso2 or -4IE 914409 1169U.WPF It is implicit in this application that the tetrazole moiety consists of the tautomeric structures with (b) being used herein to depict the tetrazole moiety.

Pharmaceutically acceptable salts such as ammonium, sodium, potassium, alkaline earth, tetraalkylammonium and the like are encompassed by the invention.

Scheme 1 illustrates a specific embodiment of the method for preparing compounds of the invention. -5IE 914409 1169U.WPF SCHEME 1 CONM, -6IE 914409 1169U.WPF The present invention is further illustrated by the following examples which are not intended to be limiting.

Example 1 CONM, Referring to Scheme 1, 2.1 grams of compound 1 were dissolved in 50 ml. of toluene and 15 ml. of (COCl)2 was added. The mixture was stirred at room temperature for four hours. The reaction was then stopped, the solvent was removed in vacuo to produce a crude oil and 150 ml. of CH2C12 was added. The solution was then cooled to room temperature and NH3 gas was bubbled through the solution for one hour. The reaction mixture was then poured into 150 ml of water, the layers were separated and the aqueous layer was extracted three times with CH2C12. The mixture was then filtered and dried to obtain 1.45 grams of compound 2.· -7IE 914409 1169U.WPF Example 2 1.35 (2.79 m mole) grams of compound 2. were dissolved in 15 ml of CH2C12 and 2.50 grams (9.77 m mole) of Burgess reagent* * were added. The mixture was stirred at room temperature overnight and stripped of solvent to obtain 1.30 grams of compound 2· Elements Carbon Hydrogen Nitrogen Calculated 72.23 7.58 3.01 Found 72.23 7.62 3.03 + * Burgess, Reagent CH3O2CNSO^NEt3 methyl(carboxysulfamoyl)triethylammonium hydroxide inner salt. J. Org. Chem. 38 26 (1973) -8IE 914409 1169U.WPF 958.2 mg of compound 2 and 203.4 mg. of (CH3)3 Si N3 were placed in a 40 ml reaction vial which was sealed and heated to 150°C overnight. The heating was continued for an additional 44 hours for a total heating time of 64 hours. The reaction mixture was then passed through a silica column with a 5/95/1 mixture of CH3OH/CH2C12/ acetic acid. 100 mg of the product, compound 4, was obtained.

Elements Carbon Hydrogen Nitrogen Calculated Found 66.12 66.23 7.13 7.15 11.02 10.95 -9IE 914409 1169U.WPF Example 4 Synthesis of Sulfonamides A mixture of 2.9g (6mMol) of compound .1, 0.96g benzenesulfonamide, 0.96g (7.8 mMol) of 4-(dimethylamino) pyridine, l.08g (6mMol) of 1-[3-(dimethylamino)propyl]-3ethylcarbodiimide hydrochloride, 5g of 4A molecular sieves and 60 mL of dry dichloromethane was stirred at room temperature for 4 days. The reaction mixture was filtered and the filtrate was washed with IN HC1, water and brine. Evaporation of the dry (Na2SO4) solvent in vacuo afforded crude product which was purified by chromatography on silica gel (hexane/ethyl acetate/acetic acid, 65/34/1 as eluant) to afford 3.lg of product.

Microanalysis: Theory c 65.47, H 6.62, N 2.25 Found: C 65.18, H 6.67, N 2.25 -10IE 914409 1169U.WPF ,co,k (cog o A Example 5 ,CONH o Compound A (2.1g) was dissolved in dry toluene and oxalyl chloride (1.2 equivalents) added with stirring under argon. drop of DMF was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue dissolved in dry CH2C12 and ammonia gas slowly bubbled through the solution for 20 minutes. Water (100 cm3) was added and the organic layer separated, dried over magnesium sulfate and the volatiles removed in vacuo. The resulting residue was purified by silica gel chromatography to afford compound (B) as a white solid (1.8g).

Analysis: Calculated for C28H35NO6 C 69.83, H 7.32, N 2.91 Found: C 69.60, H 7.23, N 2.86 -11IE 914409 1169U.WPF Example 6 3.Og of compound B were dissolved in methylene chloride (25cm3) containing Burgess reagent (4.0g) and the mixture stirred at room temperature overnight. At this point, the solvent was removed and the residue purified by chromatography on silica gel using ethyl acetate/hexane (2:8) as eluant. Compound (C) was isolated as a colorless oil (2.8g).

Example 7 NiN, Ei»N HO 1 -ooBlhyl 2· pyrrolidone Compound (C) (2.8g), sodium azide (1.2g) and triethylamine hydrochloride (1.2g) were dissolved in l-methyl 2-pyrrolidone (60cm3) and the solution heated at 150°C for 2 hours. The mixture was poured into 200cm3 of water, acidified with dilute -12IE 914409 1169U.WPF HCl and then extracted with ethyl acetate. The organic layers were dried and evaporated in vacuo to afford a crude residue which was purified by chromatography on silica gel using ethyl acetate/hexane/acetic acid (50:49:1) as solvent. Compound (D) was obtained as a white solid (2.1g).

Analysis for C28H34N4O5 Calculated: C 66.39, H 6.76, N 11.06 Found: C 66.19, H 6.87, N 11.26 Example 8 E Compound (E), (l.Og) was converted to the amide, compound, (F) as illustrated in Example 5. l.Og of compound (F) was obtained after chromatography of the crude product on silica gel using ethyl acetate/hexane (3:7) as eluant. -13IE 914409 1169U.WPF Example 9 Compound F, (l.Og) was treated with Burgess reagent under the conditions described in Example 6. The crude product thus obtained was purified by chromatography on silica gel using hexane/ethyl acetate (2:8) as eluant. Compound G (870mgs) was isolated as a colorless oil.

Micro Analysis for C29H35NO5 Calculated: C 72.93, H 7.39, N 2.93 Found: C 72.45, H 7.30, N 2.90 Example 10 Compound G (0.8g) was converted to the tetrazole H by treatment with sodium azide (330mgs), triethylamine hydrochloride (0.3g) in -14IE 914409 1169U.WPF 1-methyl 2-pyrrolidone (20cm3) . The mixture was heated at 150°C for 2 hours and then partitioned between 2N HCl and ethyl acetate. The organic layer was removed, dried (MgSO4) and stripped in vacuo to afford a crude oil. This material was purified by chromatography on silica gel (ethyl acetate/hexane/acetic acid (50:49:1) as eluant) to provide 720 mgs. of compound H.

Micro Analysis for C29H36N4O5 Calculated: C 66.90, H 6.97, N 10.76 Found: C 66.54, H 6.93, N 10.88 -15IE 914409 1169U.WPF The biological activity of the compounds of this invention was determined by the following test procedures.

Preparation of Human Neutrophils Neutrophils were purified from venous blood of normal human donors using standard techniques of dextran sedimentation, centrifugation on Ficoll-paque® (Pharmacia) or Histopaque® sterile solution (Sigma) and hypotonic lysis of erythrocytes (Boyum, A., Isolation of Leukocytes from Human Blood: Further Observations. Scand. J. Lab. Clin. Invest.. 21 (Suppl. 97): 31, 1968). The purity of isolated neutrophils was >95%.

Human Neutrophil Deqranulation Assay Neutrophil degranulation was determined by measuring the release of myeloperoxidase activity into the incubation medium. Neutrophils (3 χ 106) in 1 ml HBSS solution were preincubated with cytochalasin B(5 Mg) at 37°C for 5 minutes, followed by preincubation with test compounds for 7 minutes. Neutrophils were then incubated for 2 to 20 minutes with LTB4(5 x 10-8M) to induce degranulation. Following incubation, samples were centrifuged and myeloperoxidase was extracted from the cell pellets by sonication in phosphate buffer containing 0.4% Triton X-100. Triton X-100 was also added to the supernatants to a concentration of 0.4%. The supernatants and the pellet -16IE 914409 1169U.WPF extracts were then assayed spectrophotometrically for myeloperoxidase activity by determining the rate of decomposition of H2O2 with o-dianisidine as hydrogen donor as described by Renlund, et al. (Renlund, D. G., MacFarlane, J. L. , Christensen, R. D., Lynch, R. E., and Rothstein, G., A Quantitative and Sensitive Method for Measurement of Myeloperoxidase. Clinical Research 28:75A, 1980).

Myeloperoxidase activity released into the supernatant was expressed as the percent of the average total activity (pellet plus supernatant).

LTB4 Receptor Binding Assay Neutrophils (4 - 6X106) in 1ml Hanks' balanced salt solution containing 10 mM HEPES buffer (HBSS), pH 7.4 and 30 μΜ nordihydroguaiaretic acid were incubated with 0.6xl0-9 M (3H) LTB4 in the presence or absence of test compounds. The incubation was carried out at 0°C for 45 minutes and terminated by adding 5ml of ice-cold HBSS followed by rapid filtration of incubation mixture under vacuum through GF/C glass fiber filters. The filters were further washed with 10ml HBSS and radioactivity was determined. Specific binding was defined as the difference -17IE 914409 1169U.WPF between total binding and nonspecific binding which was not displaced by 10-7M unlabeled LTB4. All data refer to specific binding.

Modified Boyden Chamber Chemotaxis Human neutrophils were isolated from citrated peripheral blood using standard techniques of dextran sedimentation, followed by centrifugation on Histopaque® sterile solution (Sigma) or Ficoll-paque® (Pharmacia) and hypotonic lysis of erythrocytes. A final cell suspension of 3.4 X 106 neutrophils/ml of HEPES-buffered Hanks balanced salt solution (HBSS, pH 7.3) was added to the upper well (0.8 ml) of a modified Boyden chamber (blind well). The lower well (0.2 ml), separated by a polycarbonate membrane (Nuleopore Corp.), contained HBSS or 3 X 10_8M LTB4 in the presence of absence of test compound. Following a 90 minute incubation at 37° C in 5% CO2~95% air, cells from the lower well were lysed and nuclei counted in a Model S-Plus—IV Coulter Counter. Percent inhibition was calculated from cell counts corrected for random migration by subtracting the mean of the HBSS control.

The compounds of this invention can be administered in a number of dosage forms. A preferred method of delivery would be oral or in such a manner so as to localize the action of the inhibitor. In an inflammatory condition such as rheumatoid -18IE 914409 1169U.WPF arthritis the compounds could be injected directly into the affected joint. The compounds could also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. They may be introduced intraperitoneally, subcutaneously, or intramuscularly using forms known to the pharmaceutical art. Topical application in the form of salves and ointments are useful for treating psoriasis. Regardless of the route of administration selected, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.

Results for representative compounds of the invention are shown in Table 1.

Data are expressed as potency relative to compound 1. in Scheme 1, 7-[3,(4-acetyl-3-methoxy-2-propylphenoxy) propoxy]-3,4dihydro-8-propyl-2H-l-benzopyran-2-carboxylic acid, which is disclosed generally in U.S. 4,889,871. -19IE 914409 1169U.WPF Table 1 Relative Potency Values for LTB4 Antagonists Compound LTB4 Receptor Binding Chemotaxis Degranulation R PropylR1 0 II 1.3 - CNHSO2 Ph 1.35 H \ N-N 2-Propenyl 0.8 9 Cyclopropylmethyl 22.5 Propyl -CO2H (Compound 1) 1.0 (3x10-7M) 1.0 (1.8x10-6M) 1.0 (1.5xlO-6M) Data are expressed as potency relative to a known LTB4 antagonist, compound 1 in Example 1, defined as 1.0. Values in parenthesis refer to IC50 values for compound 1. IC50 is the effective concentration needed to cause 50% inhibition. -20IE 914409 1169U.WPF The compounds of this invention can be administered in a number of dosage forms. A preferred method of delivery would be oral or in such a manner as to localize the action of the antagonist. In an inflammatory condition such as rheumatoid arthritis, the compounds could be injected directly into the affected joint. The compounds could also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. They may be introduced intraperitoneally, subcutaneously, or intramuscularly using forms known to the pharmaceutical art. Topical application in the form of salves and ointments is useful for treating psoriasis. Regardless of the route of administration selected, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.

In general, a unit dosage of a compound of the invention would contain from about 50 mg to about 500 mg of the active ingredient with from about 70 mg to about 300 mg preferred.

An effective but non-toxic quantity of the compound is employed in treatment. The dosage regimen for antagonism of LTB4 by the compounds of this invention is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the mammal, the particular disease and its severity, the route of administration and the particular compound employed. An ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount of the compound to prevent or arrest the progress -21IE 914409 1169U.WPF of the condition. In so proceeding, the physician or veterinarian could employ or use relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained. Generally, a dosage range of 1 to 25 mg/kg of body weight is administered to patients in need of treatment for inflammatory conditions.

Claims

What is claimed is:

1. A compound of the formula and the stereoisomers and pharmaceutically acceptable salts thereof, wherein R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; R x is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is lower alkyl, phenyl, unsubstituted or substituted with lower alkyl; H or \ N-N •V : and n is an integer from 2 to 5. -23IE 914409 1169U.WPF

2. A compound of Claim 1 wherein R is lower alkyl of 1 to 6 carbon atoms or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is l, 2 or 3; II and R 3 is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is phenyl, unsubstituted or substituted with lower alkyl; or H \ N-N and n is 3, 4 or 5.

3. A compound of Claim 2 wherein R is propyl, 2-propenyl or cyc 1 opropyImethy 1; R-, is -CONH 2 , -C-NHSO 2 R 2 · or ; R 2 is phenyl; or 5 . Claim 3 wherein R is 2-propenyl; R 3 is and n is 3, 4

4. A compound of -24IE 914409 1169U.WPF

5. A compound of Claim 3 wherein R is cyclopropyImethyl; R x and n is 3.

6. A compound of Claim 3 wherein R is propyl; Rj is and n is 3.

7. A compound of Claim 3 wherein R is propyl; Rj is O II —CNH SO 2 R 2 wherein R 2 is phenyl; and n is 3. 8. A compound of Claim 3 wherein R is cyclopropyl methyl; R 1 is -CONH 2 ; and n is 3 . 9. A compound of Claim 3 wherein R is 2-propenyl; Rj is -CONH 2 ; and n is 3 .

8. 10. A pharmaceutical composition for treating inflammatory diseases comprising a therapeutically effective amount of a compound of the formula -25IE 914409 1169U.WPF R and the stereoisomers and pharmaceutically acceptable salts thereof, wherein R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; Rj is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is lower alkyl, phenyl, unsubstituted or substituted with lower alkyl; or and n is an integer from 2 to 5, and a pharmaceutically acceptable carrier.

9. 11. The pharmaceutical composition of Claim 10 wherein R is lower alkyl of 1 to 6 carbon atoms or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is -26IE 914409 1169U.WPF 1, 2 or 3; and R x is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is phenyl, unsubstituted or substituted with lower alkyl; or

10. 12. // and n is 3, 4 or 5. The pharmaceutical composition of Claim 11 wherein R is propyl, 2-propenyl or cyclopropylmethyl; R x is -CNHSO 2 R 2 and n is 3, 4 or 5. ; R 2 is phenyl or

11. 13. The pharmaceutical composition of Claim 12 wherein R is 2-propenyl; Rj is and n is 3.

12. 14. The pharmaceutical composition of Claim 12 wherein R is cyclopropylmethyl; Rj is 'N I :N and n is 3. -27IE 914409 1169U.WPF

13. 15. The pharmaceutical composition of Claim 12 wherein R is propyl; Rj_ is N and n is 3.

14. 16. The pharmaceutical composition of Claim 12 wherein R is propyl; R·· is 0 -CNHSO 2 R 2 wherein R 2 is phenyl; and n is 3.

15. 17. The pharmaceutical composition of Claim 12 wherein R is cyclopropyl methyl; Rj^ is -CONH 2 ; and n is 3.

16. 18. The pharmaceutical composition of Claim 12 wherein R is 2-propenyl; Rj^ is -CONH 2 , and n is 3.

17. 19. A method of treating leukotriene B 4 mediated diseases comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula the stereoisomers and pharmaceutically acceptable salts -28IE 914409 1169U.WPF thereof, wherein R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; R 1 is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is lower alkyl, phenyl, unsubstituted or substituted with lower alkyl; or \ N-N and n is an integer from 3, 4 to 5.

18. 20. The method of Claim 19 wherein R is lower alkyl of 1 to 6 carbon atoms or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; and R x is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is phenyl, unsubstituted or substituted with lower alkyl; or and n is 3, 4 or 5. -29IE 914409 1169U.WPF

19. 21. A method of treating inflammatory diseases comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula ? 1 the stereoisomers and pharmaceutically acceptable salts thereof, wherein R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or (CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; II Rj is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is lower alkyl, phenyl, unsubstituted or substituted with lower alkyl; or and n is an integer from 2 to 5. -30IE 914409 1169U.WPF

20. 22. The method of Claim 21 wherein R is lower alkyl of 1 to 6 carbon atoms or -(CH 2 )m R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3; and O II R 3 is -CONH 2 or -C-NHSO 2 R 2 wherein R 2 is phenyl, unsubstituted or substituted with lower alkyl; or // -N' I iN and n is 3, 4 or 5.

21. 23. The method of Claim 22 wherein R is propyl, 2-propenyl O II or cyclopropylmethyl; Rj is -CNHSO 2 R 2 or N--N''''* ; R 2 1S Phenyl; and n is 3

22. 24. The method of Claim 22 wherein R is 2-propenyl; Rj is 'Ν I ;N and n is 3. -31IE 914409 1169U.WPF

23. 25. The method of Claim 22 wherein R is cyclopropylmethyl; and n is 3.

24. 26. The method of Claim 22 wherein R is propyl; R x is and n is 3.

25. 27. The method of Claim 22 wherein R is propyl; R·^ is O II -CNHSO 2 R 2 ; R 2 is phenyl; and n is 3.

26. 28. The method of Claim 22 wherein R is cyclopropyl methyl R is -CONH 2 ; and n is 3.

27. 29. The method of Claim 22 wherein R is 2-propenyl; R 1 is -C0NH 2 ; and n is 3. -32IE 914409 29. A compound of the formula given and defined in Claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.

28. 30. A pharmaceutical composition according to Claim 10, substantially as hereinbefore described.

29. 31. A process for preparing a compound of the formula given and defined in Claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.

30. 32. A compound of the formula given and defined in Claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in Claim 31.