WO1993014771A1 - Macrocyclic compounds in the prophylactic treatment of aids - Google Patents
Macrocyclic compounds in the prophylactic treatment of aids Download PDFInfo
- Publication number
- WO1993014771A1 WO1993014771A1 PCT/GB1993/000207 GB9300207W WO9314771A1 WO 1993014771 A1 WO1993014771 A1 WO 1993014771A1 GB 9300207 W GB9300207 W GB 9300207W WO 9314771 A1 WO9314771 A1 WO 9314771A1
- Authority
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- WIPO (PCT)
- Prior art keywords
- octacos
- dioxa
- ene
- tetramethyl
- azatricyclo
- Prior art date
Links
- 238000011321 prophylaxis Methods 0.000 title claims abstract description 11
- 150000002678 macrocyclic compounds Chemical class 0.000 title description 3
- 208000030507 AIDS Diseases 0.000 claims abstract description 18
- NZDSHKLZMIAWFR-UHFFFAOYSA-N 12-(1-cyclohexylprop-1-en-2-yl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene Chemical compound O1CC2CCCCN2CCC(O2)C(C)CCC2CCC(C)CC(C)=CCCCCC(C)C1C(C)=CC1CCCCC1 NZDSHKLZMIAWFR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 17
- CFZGEMKIQUVTCC-UHFFFAOYSA-N octacos-18-ene-2,3,10,16-tetrone Chemical compound CCCCCCCCCC=CCC(=O)CCCCCC(=O)CCCCCCC(=O)C(C)=O CFZGEMKIQUVTCC-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- JQTZATZJTOJHSQ-UHFFFAOYSA-N octacos-10-ene Chemical compound CCCCCCCCCCCCCCCCCC=CCCCCCCCCC JQTZATZJTOJHSQ-UHFFFAOYSA-N 0.000 claims description 2
- YZLHHMXIWHDZLH-UHFFFAOYSA-N octacos-18-ene-3,10-dione Chemical compound CCCCCCCCCC=CCCCCCCCC(=O)CCCCCCC(=O)CC YZLHHMXIWHDZLH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- VZFNJGWWOQJTAX-UHFFFAOYSA-N 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone Chemical compound C1CC(C)CC(C)=CCC(=O)CCC(C)COC(=O)C2CCCCN2C(=O)C(=O)C2C(C)CCC1O2 VZFNJGWWOQJTAX-UHFFFAOYSA-N 0.000 claims 1
- 230000001861 immunosuppressant effect Effects 0.000 claims 1
- AJZKXUWKGMUCJR-UHFFFAOYSA-N octacos-18-ene-3,10,16-trione Chemical compound CCCCCCCCCC=CCC(=O)CCCCCC(=O)CCCCCCC(=O)CC AJZKXUWKGMUCJR-UHFFFAOYSA-N 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 9
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 6
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 0 CC(CCC1=*)CC1=* Chemical compound CC(CCC1=*)CC1=* 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- -1 propylene glycol) Chemical compound 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
Definitions
- This invention relates to a new use of known macrocvclic compounds in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS).
- AIDS acquired immunodeficiency syndrome
- AIDS is characterized by a degeneration of the patient's immune system, making the patient susceptible to opportunistic infections such as pneumonia which generally lead to death.
- HIN human immunodeficiency virus
- the drugs presently administered to patients infected with HIN and to patients suffering i5 from AIDS include 3'-azido-3'-deoxythymidine (AZT, Retrovir), which interferes with viral replication.
- AZT 3'-azido-3'-deoxythymidine
- patients infected with HIN who are treated with AZT generally go on to develop AIDS eventually.
- European Patent Application 184162 discloses a number of macrocvclic compounds which are indicated as immunosuppressants.
- the compounds may be described as derivatives and homologues of the basic structure 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene, and include JO 17-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene- 2,3,10,16-tetraone (FR-900506, FK 506) and 16-allyl-l,13-dihydroxy-ll-[2-
- a group of such derivatives or homologues which may be mentioned are those having immunosuppressive activity. It is especially unexpected that compounds having this activity find utility in the prophylaxis of AIDS.
- R 1 and R 2 represent two vicinal hydrogen atoms, or form a second bond between the vicinal carbon atoms to which they are attached;
- R 7 represents H, OH, protected hydroxy or alkoxy C ;
- R 10 represents alkyl C, ⁇ or alkenyl C ⁇
- X represents O, (H,H), (H,OH) or -CH 2 0-;
- Y represents O, N-NR n R 12 or N-OR 13 ;
- R u and R 12 independently represent H, alkyl C ⁇ , phenyl or tosyl; R 13 represents H or alkyl C w ;
- R 20 and R 21 independently represent O, or they may independently represent (R ⁇ a.H) and (R 21 a,H) respectively;
- R 20 a and R 21 a independently represent OH, protected hydroxy, alkoxy C w or OCH 2 OCH 2 CH 2 OCH 3 ; in addition R ⁇ a and R 21 a may together represent an oxygen atom in an epoxide ring;
- R 23 represents H;
- n is 1 or 2; in addition to their significances above, Y, R 10 and R 23 , together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl C ⁇ , hydroxy, alkyl C w substituted by one or more hydroxy groups, alkoxy C ⁇ , benzyl and -CH 2 Se(C 6 H 5 ); in addition, when the vicinal pair of substituents
- compositions of formula I include acid addition salts (for example hydrochloride), of any amine groups present.
- Preferred groups of compounds of formula I include those in which: R 10 represents methyl, ethyl, propyl or allyl; at least one of R ⁇ a and R 21 a represents OH or OCH 3 ; n is 2; any ring formed by Y, R 10 and R 23 is a pyrrole or tetrahydrofuran ring; and
- R 7 is H or OH.
- the derivatives and homologues for use in the invention may be administered by any convenient means.
- they may be introduced parenterally by injection eg intravenously, intramuscularly or subcutaneously; orally; by inhalation eg in the form of s a pressurised or non-pressurised powder formulation; topically; or by plasmapheresis.
- Suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, starch, talc or stearic acid; 0 for i ⁇ jectable solutions - water, alcohols, glycerin or vegetable oils; for inhalation compositions - lactose.
- compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings.
- solubilisers eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
- sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
- sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
- sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as
- the dosage administered will vary with the compound employed and the mode of administration. However, in general, satisfactory results are obtained when the o compounds are administered at a dosage which produces a concentration in the blood stream of from 0.1-150 ⁇ g/ml, preferably l-150 ⁇ g/ml.
- the indicated total daily dosage is in the range of from O.lmg to 3000mg and preferably from lmg to 2000mg, which may be administered, for example, in divided doses from 1 to 6 times a day or in sustained release form.
- a method of prophylaxis of AIDS which comprises administering a therapeutically effective amount of a derivative or homologue of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.0 4,9 ]octacos-18-ene to a patient infected with HIN.
- the biological activity of the derivatives and homologues for use in the invention may be demonstrated using the methods disclosed by Karpas et al, Proc ⁇ atl Acad Sci USA, 89, pp8351-8355.
- Karpas et al demonstrated therein that FR-900506 interferes with HIN production and selectively inhibits the growth of uninfected cells.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There is provided the use of derivatives and homologues of 12-(2-cyclohexyl-1-methylvinyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene in the prophylactic treatment of AIDS.
Description
Macrocvclic compounds in the prophylactic treatment of AIDS
This invention relates to a new use of known macrocvclic compounds in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS).
5
AIDS is characterized by a degeneration of the patient's immune system, making the patient susceptible to opportunistic infections such as pneumonia which generally lead to death.
iϋ Current theory suggests that the human immunodeficiency virus (HIN) causes AIDS. However, patients infected with HIN can remain healthy for several years before developing the symptoms of AIDS.
The drugs presently administered to patients infected with HIN and to patients suffering i5 from AIDS include 3'-azido-3'-deoxythymidine (AZT, Retrovir), which interferes with viral replication. However, it is frequently toxic, and after a few months of treatment AZT-resistant mutants of HIN appear (Karpas et al, Proc Νatl Acad Sci USA, 89, pp8351-8355). Furthermore, patients infected with HIN who are treated with AZT generally go on to develop AIDS eventually.
20
There is therefore a need for a drug which is effective or more effective in the prophylactic treatment of AIDS (by which we mean that the treatment defers the onset of AIDS in patients infected with HIN), which is less toxic than current therapies, and which can be used in patients who have grown resistant to treatment with AZT.
25
European Patent Application 184162 discloses a number of macrocvclic compounds which are indicated as immunosuppressants. The compounds may be described as derivatives and homologues of the basic structure 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene, and include JO 17-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone (FR-900506, FK 506) and 16-allyl-l,13-dihydroxy-ll-[2-(4-hydroxy-3- methoxycyclohexyl)-l-methylvinyl]-22,24-dimethoxy-12,18,20,26-tetramethyl-10.27-dioxa-4-
azatricyclo [21.3.1.0 ,8]octacos-17-ene-2,3,9,15-tetraone (FR-900525). Many other macrocyclic compounds of this class have since been disclosed, both synthetically derived from the compounds of European Patent Application 184162 (see International Patent Application WO 89/05304) and from fermentation (see European Patent Applications s 349049 and 349061).
International Patent Application No WO 91/04025 discloses a number of macrocyclic compounds believed to be antagonists of the compound FR-900506 in the treatment of diseases involving immunodepression, and AIDS is mentioned generally. However, there o is no suggestion of any prophylactic activity.
It has now been found that derivatives or homologues of the basic structure 12-(2- cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricycio[22.3.1.04'9] octacos-18-ene are useful in the prophylactic treatment of AIDS. 5
Thus, according to the present invention, there is provided the use of a derivative or homologue of l2-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.L04,9]octacos-18-ene as active ingredient in the manufacture of a medicament for the prophylactic treatment of AIDS.
A group of such derivatives or homologues which may be mentioned are those having immunosuppressive activity. It is especially unexpected that compounds having this activity find utility in the prophylaxis of AIDS.
s A preferred group of derivatives or homologues which may be mentioned are the compounds of formula I,
wherein the vicinal pair of substituents [R1 and R2] represent two vicinal hydrogen atoms, or form a second bond between the vicinal carbon atoms to which they are attached; R7 represents H, OH, protected hydroxy or alkoxy C ;
R10 represents alkyl C,^ or alkenyl C^;
X represents O, (H,H), (H,OH) or -CH20-;
Y represents O, N-NRnR12 or N-OR13;
Ru and R12 independently represent H, alkyl C^, phenyl or tosyl; R13 represents H or alkyl Cw;
R20 and R21 independently represent O, or they may independently represent (R^a.H) and (R21a,H) respectively; R20a and R21a independently represent OH, protected hydroxy, alkoxy Cw or OCH2OCH2CH2OCH3; in addition R^a and R21a may together represent an oxygen atom in an epoxide ring; R23 represents H; n is 1 or 2;
in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl C^, hydroxy, alkyl Cw substituted by one or more hydroxy groups, alkoxy C^, benzyl and -CH2Se(C6H5); in addition, when the vicinal pair of substituents [Rl and R2] represent two vicinal hydrogen atoms, then R7 and Y may together represent the group -0-N(0)m= wherein the N atom is bonded to C16 and m is 0 or 1; and pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts (for example hydrochloride), of any amine groups present.
Compounds of formula I in which X is (H,H) are known from International Patent Application No WO 91/02736. Compounds of formula I in which R7 and Y together represent the group -0-N(0)m= are known from International Patent Application No WO 92/03441.
Preferred groups of compounds of formula I include those in which: R10 represents methyl, ethyl, propyl or allyl; at least one of R^a and R21a represents OH or OCH3; n is 2; any ring formed by Y, R10 and R23 is a pyrrole or tetrahydrofuran ring; and
R7 is H or OH.
Specific derivatives of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl-11.2S- dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene which may be mentioned include: 17-Allyl- 1, 14,20-trihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)- l-methylvinyI]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 ,9]octacos-18-ene- 2.3,10,16-tetraone,
17-Ethyl-l,14,20-trihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-l-methyIvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone,
17-( l-Hydroxyprop-2-enyl)-l, 14,20-trihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)- 1- m ethylvinyl]- 23,25-dimethoxy- 13, 19,21,27-tetramethyl- l l,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
17-(2,3-Dihydroxypropyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l- methylvinyl] -23 ,25-dimethoxy- 13, 19,21,27-tetramethyl- l l ,28-dioxa-4- azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
17-Ethanah/l-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-
2,3,10,16-tetraone, 17-Allyl-l,2,14,16-tetrahydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-
23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22,3.1.04'9]octacos-18- ene-3,10-dione, and
17-(2-Oxopropyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-
23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04' ]octacos-18- ene-2,3,10,16-tetraone, this latter compound being of particular interest.
Specific immunosuppressive derivatives of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 '9]octacos-18-ene which may be mentioned include:
17-Allyl-l,2,14-trihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-
3,10,16-trione,
17-Propyl-l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-
2,3,10,16-tetraone,
17- yl-l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23.25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-2,3, 10,16- tetraone, 17-Ethyl-l,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-2,3,10,16- tetraone,
17-Allyl-l,14-dihydroxy-12-[2-(3,4-dihydroxyc^clohexyl)-l-methylvinyl]-23,25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricycIo[22.3.1.04-9]octacos-18-ene-2,3,10,16- tetraone,
17-Ethyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- s dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri(7clo[22.3.1.04' ]octacos-18-ene-
2,3,10,16-tetraone (FR-900520), and
17-Allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 ,9]octacos-18-ene-
2,3,10,16-tetraone (FR-900506), o this latter compound being of particular interest.
The derivatives and homologues for use in the invention may be administered by any convenient means. For example, they may be introduced parenterally by injection eg intravenously, intramuscularly or subcutaneously; orally; by inhalation eg in the form of s a pressurised or non-pressurised powder formulation; topically; or by plasmapheresis.
Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, starch, talc or stearic acid; 0 for iηjectable solutions - water, alcohols, glycerin or vegetable oils; for inhalation compositions - lactose.
The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form.
The dosage administered will vary with the compound employed and the mode of administration. However, in general, satisfactory results are obtained when the o compounds are administered at a dosage which produces a concentration in the blood stream of from 0.1-150μg/ml, preferably l-150μg/ml.
For man the indicated total daily dosage is in the range of from O.lmg to 3000mg and preferably from lmg to 2000mg, which may be administered, for example, in divided doses from 1 to 6 times a day or in sustained release form.
s According to a further aspect of the invention, there is provided a method of prophylaxis of AIDS, which comprises administering a therapeutically effective amount of a derivative or homologue of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene to a patient infected with HIN.
o Biological Activity
The biological activity of the derivatives and homologues for use in the invention may be demonstrated using the methods disclosed by Karpas et al, Proc Νatl Acad Sci USA, 89, pp8351-8355. Karpas et al demonstrated therein that FR-900506 interferes with HIN production and selectively inhibits the growth of uninfected cells.
Claims
1. The use of a derivative or homologue of 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene as active ingredient in the manufacture of a medicament for the prophylactic treatment of AIDS.
2. The use as claimed in claim 1, wherein the derivative is an immunosuppressant.
3. The use as claimed in claim 1 or claim 2, wherein the derivative is a compound of formula I,
wherein the vicinal pair of substituents [R1 and R2] represent two vicinal hydrogen atoms, or form a second bond between the vicinal carbon atoms to which they are attached; R7 represents H, OH, protected hydroxy or alkoxy C^; R10 represents alkyl C^ or alkenyl C^; X represents O, (H,H), (H,OH) or -CH20-;
Y represents O, N-NRnR12 or N-OR13;
Ru and R12 independently represent H, alkyl C^, phenyl or tosyl;
R13 represents H or alkyl Cw; R20 and R21 independently represent O, or they may independently represent (R^a-H) and (R21a,H) respectively; R20a and R21a independently represent OH, protected hydroxy, alkoxy Cw or OCH2OCH2CH2OCH3; in addition R^a and R21a may together represent an oxygen atom in an epoxide ring;
R23 represents H; n is 1 or 2; in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S^ or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl C,^, hydroxy, alkyl Cw substituted by one or more hydroxy groups, alkoxy C,^, benzyl and -CH2Se(C6Hs); in addition, when the vicinal pair of substituents [R1 and R2] represent two vicinal hydrogen atoms, then R7 and Y may together represent the group -0-N(0)m= wherein the N atom is bonded to C16 and m is 0 or 1; or a pharmaceutically acceptable salt thereof.
4. The use as claimed in claim 3, wherein R10 represents methyl, ethyl, propyl or allyl.
5. The use as claimed in claim 3 or claim 4, wherein at least one of R^a and R21a represents OH or OCH3.
6. The use as claimed in any one of claims 3 to 5, wherein n is 2.
7. The use as claimed in claim 3, wherein any ring formed by Y, R10 and R23 is a pyrrole or tetrahydrofuran ring.
8. The use as claimed in claim 1, wherein the derivative of 12-(2-cyclohexyl-l- methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene is: 17-Allyl-l,14,20-trih.ydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- s dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-
2,3, 10, 16-tetraone,
17-Ethyl-l,14,20-trihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 -9]octacos-18-ene-
2,3,10,16-tetraone, o 17-(l-Hydrθ3gφrop-2-enyl)-l,14,20-trihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyI)-l- methylvinyl]-23,25-dimethoxy- 13, 19,21, 27-tetramethyl-l l,28-dioxa-4- azatricyclo[22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-(2,3-Dihydroxypfopyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l- methylvinyl] -23 ,25-dimethoxy- 13, 19,21, 27-tetramethyl- l l,28-dioxa-4- s azatricyclo[22.3.1.04*9]octacos-18-ene-2,3,10,16-tetraone,
17-Ethanahl-l,14-dfliydro3Q'-12-[2-(4-hydro^-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04-9]octacos-18-ene-
2,3,10,16-tetraone,
17-Allyl-l,2,14,16-tetrahydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyI)-l-methylvinyl]- u 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 ,9]octacos-18- ene-3,10-dione, or
17-(2-Oxopropyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methyi\'inyrj-
23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18- ene-2,3, 10, 16-tetraone. S
9. The use as claimed in any one of claims 1 to 3, wherein the derivative of 12-(2- cyclohexyI-l-methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9] octacos-18-ene is: 17-Allyl-l,2,14-trihydroxy-12-[2-(4-hydroxy-3-methoxy(^clohexyl)-l-methylvinyl]-23,25-
3o dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 3,10,16-trione, 17-Proρyl-l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-
2,3,10,16-tetraone,
17-Allyl-l-hydro-^-12-[2-(4-hydroxy-3-memoxycyclohexyl)-l-methylvinyl]-23,25-cIimethσxy- 5 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16- tetraone,
17-Ethyl-l,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-2,3,10,16- tetraone, ιo 17-Allyl-l,14-dihydroxy-12-[2-(3,4-dihydroxyc^clohexyl)-l-methylvinyl]-23,25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16- tetraone,
17-Ethyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene- i5 2,3,10,16-tetraone; or
17-Allyl- 1, 14-dihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 ,9]octacos-18-ene-
2,3,10,16-tetraone.
20 10. A method of prophylaxis of AIDS, which comprises administering a therapeutically effective amount of a derivative or homologue of 12-(2-cyclohexyl-l- methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9 octacos-18-ene to a patient infected with HIN.
25
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929202196A GB9202196D0 (en) | 1992-02-01 | 1992-02-01 | Method of treatment |
| GB9202196.3 | 1992-02-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993014771A1 true WO1993014771A1 (en) | 1993-08-05 |
Family
ID=10709693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1993/000207 WO1993014771A1 (en) | 1992-02-01 | 1993-02-01 | Macrocyclic compounds in the prophylactic treatment of aids |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU3456793A (en) |
| GB (1) | GB9202196D0 (en) |
| WO (1) | WO1993014771A1 (en) |
| ZA (1) | ZA93691B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001005385A3 (en) * | 1999-07-21 | 2001-08-02 | Fujisawa Pharmaceutical Co | New use of a macrolide compound for treating neurodegenerative disorders |
| EP1353671A4 (en) * | 2000-12-29 | 2004-07-14 | Fujisawa Pharmaceutical Co | Neurotrophic tacrolimus analogs |
| WO2005067928A1 (en) * | 2004-01-20 | 2005-07-28 | Astellas Pharma Inc. | Method for treating erectile dysfunction |
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
| US10259827B2 (en) | 2016-11-10 | 2019-04-16 | Novartis Ag | BMP potentiators |
-
1992
- 1992-02-01 GB GB929202196A patent/GB9202196D0/en active Pending
-
1993
- 1993-02-01 ZA ZA93691A patent/ZA93691B/en unknown
- 1993-02-01 WO PCT/GB1993/000207 patent/WO1993014771A1/en active Application Filing
- 1993-02-01 AU AU34567/93A patent/AU3456793A/en not_active Abandoned
Non-Patent Citations (2)
| Title |
|---|
| AIDS RES. HUM. RETROVIRUSES vol. 8, no. 5, 1992, page 910 P. H\LLSBERG ET AL. 'HTLV-I induced spontaneous T-cell clonal proliferation is rapamycin sensitive' * |
| PROC. NATL. ACAD. SCI. USA vol. 89, September 1992, pages 8531 - 8355 A. KARPAS ET AL. 'Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506' cited in the application * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001005385A3 (en) * | 1999-07-21 | 2001-08-02 | Fujisawa Pharmaceutical Co | New use of a macrolide compound for treating neurodegenerative disorders |
| EP1353671A4 (en) * | 2000-12-29 | 2004-07-14 | Fujisawa Pharmaceutical Co | Neurotrophic tacrolimus analogs |
| WO2005067928A1 (en) * | 2004-01-20 | 2005-07-28 | Astellas Pharma Inc. | Method for treating erectile dysfunction |
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
| US10259827B2 (en) | 2016-11-10 | 2019-04-16 | Novartis Ag | BMP potentiators |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA93691B (en) | 1993-09-06 |
| AU3456793A (en) | 1993-09-01 |
| GB9202196D0 (en) | 1992-03-18 |
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