GB1560942A - 10,10,-dimethyl-12-azaprostaglandins - Google Patents
10,10,-dimethyl-12-azaprostaglandins Download PDFInfo
- Publication number
- GB1560942A GB1560942A GB43989/75A GB4398975A GB1560942A GB 1560942 A GB1560942 A GB 1560942A GB 43989/75 A GB43989/75 A GB 43989/75A GB 4398975 A GB4398975 A GB 4398975A GB 1560942 A GB1560942 A GB 1560942A
- Authority
- GB
- United Kingdom
- Prior art keywords
- hydrogen
- compound according
- group
- formula
- alkyl
- Prior art date
- 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.)
- Expired
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- 150000001875 compounds Chemical class 0.000 claims description 160
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 239000001257 hydrogen Substances 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 73
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- -1 methoxy, ethoxy Chemical group 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 230000009102 absorption Effects 0.000 claims description 18
- 238000010521 absorption reaction Methods 0.000 claims description 18
- 125000004185 ester group Chemical group 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 16
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 9
- 230000000144 pharmacologic effect Effects 0.000 claims description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 8
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 8
- 238000007069 methylation reaction Methods 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 230000011987 methylation Effects 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 206010006482 Bronchospasm Diseases 0.000 claims description 4
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- 239000000443 aerosol Substances 0.000 claims description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
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- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 claims description 2
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- 210000002784 stomach Anatomy 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 claims description 2
- 230000001988 toxicity Effects 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 2
- 102100025854 Acyl-coenzyme A thioesterase 1 Human genes 0.000 claims 1
- 101710175445 Acyl-coenzyme A thioesterase 1 Proteins 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
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- 239000000203 mixture Substances 0.000 description 18
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 241000786363 Rhampholeon spectrum Species 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 229940067597 azelate Drugs 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
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- 239000000706 filtrate Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 1
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZMINIOSEUPWFEA-UHFFFAOYSA-N diethyl 2-bromononanedioate Chemical compound CCOC(=O)CCCCCCC(Br)C(=O)OCC ZMINIOSEUPWFEA-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
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- NLMSRVZREZMYNW-UHFFFAOYSA-N ethyl 3-chloro-2,2-dimethyl-3-oxopropanoate Chemical compound CCOC(=O)C(C)(C)C(Cl)=O NLMSRVZREZMYNW-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
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- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- UPZGJLYTRBYTLM-UHFFFAOYSA-M lithium;iodide;dihydrate Chemical compound [Li+].O.O.[I-] UPZGJLYTRBYTLM-UHFFFAOYSA-M 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) 10,10-DIMETHYL-12-AZAPROSTAGLANDINS (71) We, BEECHAM GROUP LIMITED, a British Company of Beecham
House, Great West Road, Brentford, Middlesex, England, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel compounds having pharmacological activity, to processes for their preparation, to intermediates useful in that process and to pharmaceutical compositions containing them.
More specifically, this invention relates to novel 3,5-dione-4,4-dimethyl pyrrolidones 10,1 0-dimethyl- 1 2-ataprostaglandins and derivatives thereof.
Natural prostaglandins and analogues thereof are known to possess a wide variety of pharmacological activities.
British Patent Specification 1,428,431 discloses that pyrazolidine derivatives of the formula (I)':
wherein A is CH = CH or C C; R is H, or alkyl or cycloalkyl of up to 12 carbon atoms; m isO or 1; n is 04; p is OS; and Y and Z are 0 or H2 with the proviso that
Y and Z are not both 0; and alkali metal and amine salts thereof have similar biological properties to the prostaglandins or are antagonists of prostaglandins.
A paper by Bolliger and Muchowski (Tet. Letters, 1975, 2931) describes the preparation of 1 1-deoxy-8-azaprostaglandin E" but states only that one primer thereof was more active in several biological assays than the other epimer.
Our British Patent Specification No. 1,524,818 discloses that compounds of the formula (I)":
wherein: X is CO, protected CO, CROH in which R is hydrogen or C, 4 alkyl and in which the OH moiety may be protected; Y is CH2CH2 or CH = CH; Z is CO or CH2; n is 1 to 8; m is 1, 2 or 3; R, is hydrogen, CH2OH, CH2OH in which the OH moiety is protected, CO2W wherein W is hydrogen or CO2W represents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH2; R2 is hydrogen, C,, alkyl, or taken together with R2 and the carbon atoms to which it is attached represents a carbonyl group; R3 is hydrogen, hydroxy or protected hydroxy; R4 is hydrogen or C19 alkyl; and salts thereof; have useful pharmacological activity.
A novel class of compounds having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
Accordingly, the present invention provides a compound of the formula (I):
wherein: n is 4 to 8;
X is CO, protected CO or CROH wherein R is hydrogen or C,, alkyl and wherein the OH group may be protected;
R, is hydrogen, or CO2R1 represents an ester group in which the R, radical contains from 1 to 12 carbon atoms;
R3 is hydroxy or protected hydroxy;
R2 and R4 are separately hydrogen, C19 alkyl, C58 cycloalkyl, C5~8cycloalkyl-C,~B alkyl, phenyl, phenyl-C16 alkyl, naphthyl, naphthyl-C,~ alkyl, any of which phenyl or naphthyl groups may be-substituted by one or more halogen atoms or trifluoromethyl, C10 alkyl, C16 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represent C58 cycloalkyl;
A is hydrogen or a group CO2B wherein B is bydrogen, or CO2B represents an ester group in which B contains from 1 to 12 carbon atoms; or methyl; and salts thereof.
Suitably n is 5, 6 or 7, preferably 6.
Suitably protected hydroxy groups CROH and R3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl radical contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl. Preferably R3 is hydroxyl and the hydroxy group in CROH is unprotected.
Examples of suitable groups X include CO, CHOH, C(CH3)OH and C(C2H5)OH. Preferably X is CO, CHOH or C(CH3)OH, and most preferably CO.
X may also be a protected CO group. Suitable examples of such protected CO groups X include groups formed by conventional carbonyl addition and condensation reactions such as ketals, thioketals, hemithioketals, oximes, semicarbazones and hydrazones. Of such groups often the ketal type derivatives will be most useful, for example when X is a group
R, is hydrogen or CO2R1 represents an ester group in which the R1 radical contains from 1 to 12 carbon atoms. Examples of R, include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl and tolyl, while normally hydrogen or C1 4 alkyl groups are preferred.
Suitable groups R4 when R4 is an alkyl group include C49 alkyl groups. Such C49 alkyl groups may be straight chain alkyl groups, such as n-butyl, n-pentyl, nhexyl and n-heptyl, or may be alkyl groups branched by one or two methyl groups (at the same or different carbon atoms). Thus for example, R4 may be a group CH2R5, CH(CH3)R5 or C(CH3)2R5, wherein R5 is a straight chain alkyl group such that the carbon content of the resultant group R4 is 4 to 9.
In general preferred groups R4 when R4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful. Other preferred groups R4 include groups CH(CH3)R5 and C(CH3)2R5 wherein R5 is straight chain butyl, pentyl and hexyl.
When R4 is or contains a C8 8 cycloalkyl radical, the radical is suitably a cyclohexyl radical. Examples of suitable C18 alkyl radical when R4 is a C58 cycloalkyl-C1-6 alkyl group include methyl, ethyl, propyl, butyl and amyl.
When R4 is an aryl group as previously defined, suitable groups R4 include phenyl, benzyl, phenethyl, 3-phenyl-propyl, 4-phenyl-butyl, naphthyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl and 4-naphthylbutyl, and such groups branched in the alkyl radical by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl group by normally one, two or three atoms or groups selected from those substituents listed hereinbefore. Examples of suitable substituents include fluorine, chlorine and bromine atoms and CF3, methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxy and nitro groups. Preferably the aryl groups when substituted by such groups will be mono- or di-substituted.
Particularly suitable values for R2 are hydrogen, C,, alkyl and phenyl, for example hydrogen, methyl, ethyl and phenyl. Of these groups, preferred groups incude methyl and ethyl.
Otherwise R2 can suitable represent groups such as those described above as suitable and preferred groups for R4.
Also, R2 and R4 taken with the carbon atom to which they are joined can represent a C8 cycloalkyl group, such as the cyclohexyl group.
A may be hydrogen or a group CO2B. Suitable examples of B include hydrogen and methyl, ethyl, propyl, butyl, phenyl, benzyl and tolyl, while normally for B hydrogen or C14 alkyl are preferred. While the groups B and R1 may be different, it is normally preferred that they are both hydrogen or the same C14 alkyl groups. In general the most useful compounds of this sort are those wherein A is hydrogen.
Another important group of compounds of the formula (I) are those wherein A is methyl.
The compounds of the formula (I) may form conventional acid salts when R, is hydrogen. Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, and ammonium and substituted ammonium salts.
A group of compounds within the compounds of the formula (I) are defined are those wherein X is CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R2 is hydrogen, C14 alkyl or phenyl; R4 is hydrogen, C19 alkyl, phenyl, phenyl-C, 4 alkyl, naphthyl, naphthyl-C,~4 alkyl, any of which phenyl or naphthyl group may be substituted by one or more halogen atoms or trifluoromethyl, C16 alkyl, C16 alkoxy or nitro groups; and A is hydrogen or a group CO2B wherein B is hydrogen, or CO2B represents an ester group in which B contains from 1 to 12 carbon atoms; and salts thereof.
One particularly suitable sub-group of compounds within such compounds of formula (I) include those of formula (II):
wherein: p is 6 or 8;
X1 is CO, CHOH or C(CH3)OH; R'1 is hydrogen or C1 4 alkyl; R12 is hydrogen, methyl or ethyl; R14 is hydrogen or C19 alkyl; and
A' is hydrogen or a group CO2R11; and salts thereof.
In formula (II), p is most suitably 6, X1 is most suitably CO, R12 is most suitably methyl or ethyl and A' is most suitably hydrogen.
While R'4 may be hydrogen or a C19 alkyl group, it is normally a C49 alkyl group. In such cases suitable and preferred straight chain and branched groups R'4 include those previously described as suitable and preferred for the group R4 when
R4 is a C49 alkyl group. Such preferred groups R14 include straight chain pentyl, hexyl and heptyl, and of these normally the most useful is straight chain hexyl.
Other preferred groups R14 include CH(CH3)R'5 and C(CH3)2R'5 wherein R's is straight chain butyl, pentyl or hexyl.
A second sub-group of interest within such compounds of formula (I) includes compounds of the formula (III):
wherein: p, X', R'1, R'2 and A' are as defined in formula (II); and R24 is a group of formula (IV):
wherein u is a bond, or a C16 alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and
W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof.
Often u will be a group CH2) - wherein is O to 4.
In formula (III) p is most suitably 8, X' is most suitably CO, R'2 is most suitably methyl or ethyl, and A' is most suitably hydrogen. Also, W is most suitably hydrogen.
A third sub-group of compounds within such compounds of formula (I) of interest include those of formula (V):
wherein p, R11, R'2 and A' are as defined in formula (II), and R34 is a group of formula (VI):
wherein U, W, Y and Z are as defined in formula (IV); and salts thereof.
Often U will be a group (CH2)q wherein q is 0 to 4.
In formula (V) we prefer that p is 6. Most suitably X' is CO, R'2 is methyl or ethyl, and A' is hydrogen.
The sub-groups of formula (II), (III) and (V) all involve compounds wherein R'2 is hydrogen, methyl or ethyl. When R12 is phenyl, particularly interesting compounds within the formula (I) include those of the formula (11), (III) and (V) as hereinbefore defined but wherein R'2 is phenyl.
A further group of compounds of interest are those of formula (II), (III) or (V) as defined hereinbefore but wherein A' is methyl.
A fourth sub-group of compounds within formula (I) of interest include those of formula (VII):
wherein: p, X', R', and R'2 are as defined in formula (II); A" is hydrogen, or a group CO2R11, or methyl; R14 is a group of formula (VIII):
wherein U is as defined in formula (IV) and r is O to 3; and salts thereof.
Often S will be a group - (CH2)q wherein q is 0 to 6.
In formula (VII) we prefer that p is 6. Most suitably X' is CO, R'2 is methyl or ethyl, and A' is hydrogen or methyl.
A fifth sub-group of compounds within formula (I) of interest include those of formula (IX):
wherein: p, X', R' and A' are as defined in formula (VII); Rb2 and Rb4 are separately C59 alkyl or groups of formula (IV), (VI) or (VIII) as defined; or Rb2 and Rb4 taken together with the carbon atom to which they are joined represent C58 cycloalkyl; and salts thereof.
In formula (IX) we prefer that p is 6. Most suitably X' is CO, and A" is hydrogen or methyl.
Compounds as defined in the aforesaid sub-groups, but wherein X1 is a protected CO group, are also of particular utility.
The invention also provides a process for the preparation of a compound of the formula (I) wherein A is hydrogen or Co2B which process comprises the methylation of a compound of the formula (X):
wherein n, R1, R2, R3 and R4 are as defined in formula (I), and A is hydrogen or
CO2B to yield a compound of the formula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C,, alkyl Grignard reagent or C14 alkyl metallic complex when R is C14 alkyl, and then optionally protecting the
CROH hydroxy group.
The methylation is conveniently carried out by reacting the chosen compound of the formula (X) with a strong base and a source of CH3 ions in an inert solvent.
Suitable strong bases include sodium hydride, suitable sources of CH+3 ions include the methyl halides such as methyl iodide, and suitable inert solvents include benzene and the like.
The invention also provides a process for the preparation of a compound of the formula (I) wherein A is methyl, which process comprises methylating a compound of formula (I) wherein X is CO and A is hydrogen: and thereafter if desired protecting X or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C14 alkyl Grignard reagent or C14 alkyl metallic complex when R is C14 alkyl, and then optionally protecting the
CROH hydroxy group.
The methylation is suitably carried out as for a compound of formula (X) as described above but in a more polar solvent such as dimethylformamide.
After these reaction R1 may be varied by conventional de-esterification and/or esterification reactions. Similarly protected CROH and R3 hydroxy group may be deprotected by conventional methods. For example, when R2 is a benzyloxy group.
the benzyl group may readily be removed by hydrogenolysis. Thus it may be seen that 'protected hydroxy' compounds of the formula (I) are useful intermediates in the preparation of the corresponding 'free hydroxy' compounds of the formula (I).
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is protected Co may be carried out under conventional reaction conditions, for example, for carbonyl addition and condensation reactions.
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is CHOH may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is CROH in which R is C14 alkyl may be carried out by conventional Grignard or alkyl metal, (suitably alkyl lithium) reactions.
When R1 is hydrogen, salts of compounds of the formula (I) may be prepared in conventional manner, for example, by reacting the chosen compound of the formula (I) with the required base.
The preparation of the intermediates for use in the preparation of the compounds of the formula (I) will now be discussed.
When A is hydrogen in the compound of the formula (X), then this compound of the formula (X) may be prepared by the mono-methylation of a compound of formula (XI):
wherein n, R1, R2, R3 and R4 are as defined in formula (X). This monomethylation will be carried out by conventional methods such as those described above for the monomethylation of a compound of the formula (X). After the monomethylation it will often be necessary to separate the desired monomethyl compound of the formula (X) from by products formed in the reaction, and this may be done in conventional manner.
It will however normally be preferred to generate the required compound of the formula (I) wherein A is hydrogen or methyl directly from the corresponding compound of the formula (XI) by reacting this compound of the formula (Xl) with excess methylating agent under the appropriate conditions.
When A is a group CO2B as defined in the compound of the formula (X) then this compound of the formula (X) may be prepared by a process which comprises cyclising a compound of the formula (XII):
wherein n, R1, R2, R3, R4 and CO2B are as defined in formula (I), and R6 contains from 1 to 12 carbon atoms.
Most suitably R6 is a C14 alkyl group or a benzyl group or the like, and the groups R6, B and R, are the same C14 alkyl group such as the methyl or ethyl groups. Generally the cyclisation reaction takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other -OR6 or -OB group) to bring about the initial proton abstraction from the methine group. It has been found that sodium ethoxide in benzene or potassium t-butoxide in toluene, benzene or hexamethylphosphoramide give good results. Often in this cyclisation reaction a mixture of products will be obtained, and the required compound of the formula (X) wherein A is CO2B will be separated therefrom by conventional methods.
The compounds of the formula (I) wherein A is CO2B as defined may also be prepared directly by a process which comprises cyclising a compound of the formula (XIII):
wherein n, R,, R,, Rw, R, C0B and CO2R6 are as defined in formula (XII) to yield a compound of the formula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C14 alkyl Grignard reagent or C14 alkyl metallic complex when R is C,, alkyl, and then optionally protecting the CROH hydroxy group.
The cyclisation is carried out as described for the cyclisation of a compound of formula (XII) with the difference that the required compound of the formula (I) formed in the cyclisation reaction is normally the only major product of the reaction. For this reaction it is often preferred to prepare compounds of the formula (I) wherein A is CO2B as defined by this cyclisation process rather than by the cyclisation/methylation process described earlier.
After the compound of the formula (XIII) has been cyclised, the optional steps thereafter to vary X in the resultant compound of the formula (I) are carried out in the manner described earlier in the specification in relation to the monomethylation of compound (X).
The compounds of the formula (X), (Xl), (XII) and (XIII) are useful intermediates in the preparation of the compounds of the formula (1).
The compound of the formula (XI) may be prepared by a process which comprises decarboxylating a compound of the formula (XIV):
wherein n, R1, R2, R2 and R4 are as defined in formula (1).
The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example the reaction may conveniently be effected by heating the chosen compound of the formula (XIV) in a suitable solvent such as toluene or xylene.
It is frequently convenient however to generate the compound of the formula (XI) directly from an ester of the formula (XV), and often this will in fact be the preferred route:
wherein CO2R6 is a conventional ester group as defined. In such a case R6 is preferably a benzyl group or a C14 alkyl group such as methyl or ethyl. It has been found that often it is sufficient to bring about de-esterification and subsequent decarboxylation in the chosen compound of the formula (XV) simply by leaving the compound of the formula (XV) standing in an inert solvent, for example over-night.
Otherwise the desired de-esterification and decarboxylation in the chosen compound of the formula (XV) can be brought about by treatment with lithium iodide dihydrate and collidine in anhydrous solvents, for example, or by heating the chosen compound alone or preferably in a high boiling solvent such as toluene or xylene.
It will be appreciated that compounds of the formulae (XIV) and (XV) useful intermediates.
The compounds of the formula (XV) may be prepared by a process which comprises the ring closure of a compound of the formula (XVI):
in an analogous manner to the ring closure of a compound of the formula (XIII) as hereinbefore described.
The compound of the formula (XVI) is again a useful intermediate.
In the above described processes, the group CO2R1 in the appropriate intermediates will normally represent an ester group, and if acids of the formula (I) (wherein R, is hydrogen) are required they will be obtained by de-esterification of the corresponding compound of the formula (I) wherein CO2R, is an ester group.
Usually the group CO2B in the intermediates will be the same ester group as CO2R1, and for the sake of convenience the ester group CO2R" will also normally be the same ester group as CO2R,. The ester groups CO2R,/B/R are suitably C,, alkyl esters, such as methyl or ethyl esters.
It will be seen that the intermediates of the formula (XVI), (XII) and (XIII) may be represented by the common formula (XVII):
wherein L is -CH2- (to give compounds (XVI)), or -CH(CH3)- (to give compounds (XII)), or -C(CH2)2- (to give compounds XIII)).
These compounds of the formula (XVII) may be prepared by the esterification of a corresponding acid or by the reaction of a compound of the formula (XVIII):
with a reactive acylating derivative of an acid of the formula (XIX): HO2C-L-CO2H (XIX) or an ester thereof.
Suitable reactive acylating derivatives include (a) compounds of the formula (XX): R6O2C-L-CZ (XX) where Z is a group readily displaceable by an electron-rich group, examples of Z being readily displaceable group such as Cl, Br, OSO2CH3, OSO2C6H4CH2 and OCO(CH2)rnCO2R6, (b) compounds of the formula (XX) wherein Z is OH in the presence of dicyclohexyl carbodiimide as a condensing agent.
The reaction of the compound (XVIII) with the compound (XIX) or (XX) occurs under conventional acylation conditions.
The novel substituted amino acids (XVIII) are highly useful intermediates.
The compounds (XVIII) may be prepared by the reaction of an amine of the formula (XXI): H2N-C112CH2CR2R3R4 (XXI) with a compound of the formula (XXII):
where Q is a group readily displaceable by an electron rich group.
Suitable groups Q include I, Br, Cl, O.SO2CH3 and O.SO2CH4CH3.
The displacement reaction occurs under conventional reaction conditions, for example, in an alcoholic solvent in the presence of anhydrous NqCO, or pyridine.
When R2 is hydrogen or lower alkyl then the amine (XXI) can be prepared by conventional methods. However when R2 and R4 are higher alkyl or cyclic groups as defined in formula (I), then the amine is best prepared by the following reaction scheme, or a scheme chemically analogous thereto:
53 liquid ammonia R2 R2 O f( strung ammonium. base such C=O +CH3CN CH2CN R4/ as NaNH2 or Li NH2 R4 reduce, e.g.
or lithium in liAIH4 hexamethylphosphoramide (containing diethylamine) /benzene/ THF; opt. protect.
(XXT) H2N-CH2CH2C R2R3R4 It will of course be realised that the compounds of the formula (I) have asymmetric centres, and thus are capable of existing in a number of stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof. The different stereoisomeric forms may be separated one from the other by the usual methods.
Compounds within the formula (I) have useful pharmacological activity. For example compounds within the formula (I) have anti-gastric secretion activity, cardiovascular activity e.g. anti-hypertensive activity. platelet aggregation inhibition activity, affect the respiratory tract e.g. bronchodilator activity, and have anti-fertility and smooth muscle activity.
In general it may be said that compounds within the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulation of the said pharmaceutical composition will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; filler for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl phydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. The compounds of the formula (I) may also if desired be incorporated in a food-stuff, for example in the form of a biscuit.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a sui of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or propylaxis of disorders in domestic animals which comprises the administration of an effective amount of a compound of the formula (I).
The following Examples 1 to 3 and 6 to 9 illustrate the preparation of compounds of the formula (i) and their pharmacological properties.
EXAMPLE 1.
4.4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methylnonyl)
pyrrolidin - 3,5 - done.
Sodium hydride (2.91 g, 80% dispersion) was washed with hexane, blown dry under nitrogen and suspended in dry benzene (50 ml). A solution of 2-(6'-ethoxy carbonylbexyl)- 1 -(3 "-hydroxy-3 "-methylnonyl)-pyrrolidin-3,5-dione (10.0 g) in dry benzene (60 ml) was added and the mixture was stirred at room temperature under nitrogen for 1 hour.
The mixture was heated to 70" and a solution of methyl iodide (37.8 g) in dry benzene (50 ml) was added dropwise. The mixture was heated at 700 for 2 hours.
The reaction mixture was cooled and glacial acetic acid (3.26 ml) added. The mixture was filtered and the filtrate evaporated in vacuo to give a yellow oil. The product was purified by column chromatography to give 4,4-dimethyl-2-(6'-ethoxy- carbonylhexyl)-1-(3 "-hydroxy-3 "-methylnonyl)-pyrrolidin-3,5-dione as a yellow oil (3.49 g, 33% yield).
I.R. spectrum - carbonyl absorptions at 1760 cam~' 1730 cm-l and 1680 cm~'.
broad OH absorption at 3450 cm-'.
The compounds shown in Table I were similarly prepared:
TABLE 1
Compound n Rl R2 R4 1 6 CH2 CH3 n-C6HI3 2 6 C2H5 CH2 (CH2)2C6Hs 5 C2Hs CH3 n-C6Hl3 4 6 C2H, CH3 nC,H17, 5 6 CH, CH3 n-C4H9 6 6 C2H8 C2H, n-c5Hl3 7 6 C2H5 CH3 (CH2)3C6Hs 8 6 us n-C,119 CH3 n-C6HI3 9 6 C2H5 CH3 n-CsHt 10 6 C2H, -CH3 n-C7H15 11 6 C(CH3)3 CH3 n-C9H13.
12 6 C2Hs 1 CH3 CYC,H, 13 6 C2H, CH2 C,H, 14 6 C2H CH3 CH(CH3)C6Hs C,H, L 15 6 C2H, C6Hs n-CsH 16 6 C2H5 CH3 (CH2) OCH3 In each case the I.R. spectrum showed carbonyl absorptions at 1760 cm-1, 1730 cm-l and 1680 cm-' and a broad OH absorption at 340--3500 cm-'.
EXAMPLE 2.
4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 3 - hydroxy - I - (3" - hydroxy - 3 "- methylnonyl) - pyrrolidin - 5 - one.
Sodium borohydride (125 mg) was added dropwise to a solution of 4,4dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methylnonyl)pyrrolidin - 3,5 - dione (980 mg) in dry ethanol (25 ml). The mixture was stirred at room temperature for 2 hours.
The solvent was evaporated in vacuo and the residue was taken up in diethyl ether. The ethereal solution was washed with very dilute hydrochloric acid and with water, dried over magnesium sulphate and evaporated in vacuo to give a colourless oil. The product was purified by column chromatography to give 4,4 - dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 3 - hydroxy - I - (3" - hydroxy - 3" methylnonyl) - pyrrolidin - 5 - one as a colourless oil (559 mg, 57% yield).
I.R. spectrum - carbonyl absorptions at 1735 cm-l and 1665 cm strong, broad OH absorption at 3450 cm-1.
4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 3 - hydroxy - 3 - (3" - hydroxy - 3"
ethylnonyl)pyrrolidin - 5 - one was similarly prepared.
I.R. spectrum-- carbonyl absorptions at 1720 cm-' and 1660 cm-1.
broad OH absorption at 3450 cm-l.
EXAMPLE 3.
2-( 6'- Carbaxyhexyl)4, 4-dimethyl-1 3 "-methylnonyl)-pyrrolidin-3,5-dione.
A 10% solution of potassium carbonate (6.0 ml) was added to a solution of 4,4 - dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methyl
nonyl) - pyrrolidin - 3,5 - dione (900 mg) in ethanol (20 ml). The mixture was gently
refluxed for 24 hours.
The solvent was evaporated in vacuo and the residue was taken up in water.
The aqueous solution was extracted with diethyl ether and acidified with dilute
hydrochloric acid. The acid solution was extracted with diethyl ether and this
ethereal solution was washed with water, dried over magnesium sulphate and
evaporated in vacuo to give a colourless oil. The product was purified by column
chromatography to give 2-(6 '-carboxyhexyl)4,4-dimethyl-l-(3 "-hydroxy-3 "-methyl- nonylEpyrrolidin-3,5-dione as a colourless oil (586 mg 70% yield).
I.R. spectrum - carbonyl absorptions at 1760 cm-l, 1725 cm-1 and 1670 cm-l.
broad OH absorption around 3400 cm EXAMPLE 4.
D iethyl-2-[N-(3 '-benzylaxynanyl)-amina]azelate.
A solution of diethyl 2-bromoazelate (114 g) in dry ethanol (200 ml) was added
dropwise to a refluxing solution of benzyloxynonylamine (80 g) in dry ethanol (500
ml) containing a suspension of anhydrous sodium carbonate (41 g). The mixture
was refluxed with stirring for 12 hours.
The reaction mixture was filtered and the filtrate evaporated in vacuo. The
residue was taken up in diethyl ether (500 ml) and the ethereal solution was washed
with saturated brine until neutral, dried over magnesium sulphate and evaporated
in vacuo to give diethyl 2-[N-03 '-benzyloxynonyl)-amino]azelate as a yellow oil (164 g).
Analysis: C29H49NO5requires: C, 70.84%; H, 10.04%; N, 2.85%.
found: C, 71.20%; H, 10.14%; N, 2.74%.
EXAMPLE 5.
Diethyl 2 - [N - (3 ' - benzyloxynonyl) - N - '2" - methyl - 2" - ethoxycarbonyl - propionyl)- amino]azelate.
Thionyl chloride (2.35 ml) was added dropwise to a solution of monoethyl 2,2
dimethylmalonate (4.71 g) in dry benzene (40 ml) and the mixture was refluxed for 2 hours.
The resulting solution of 2-ethoxycarbonyl-2-methylpropionyl chloride was added dropwise to a solution of diethyl 2-(N-3'-benzyloxy-n-nonyl)-aminoazelate (7.05 g) in dry benzene (40 ml) containing a suspension of anhydrous sodium
carbonate (18 g). The mixture was refluxed overnight with stirring.
The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether and the ethereal solution was washed with dilute hydrochloric acid, sodium bicarbonate and with water, dried over magnesium sulphate and evaporated in vacuo to give a brown oil. The product was purified by column chromatography to give diethyl 2-[N-(3 '-benzylaxynonyl-N-(2 "-dim ethyl- 2 "-ethoxycarbanyl-prapionyl)-amina]azelate as a yellow oil (4.37 g, 48% yield).
l.R. spectrum - carbonyl absorptions at 1720 cm-l and 1640 cm~'.
NMR spectrum -5 proton singlet at 2.74 t (CeH5CH2) 2 proton singlet at 5.53 T (C,H5CH2) 2 proton quartets at 5.87 r and 5.92 T, T=12 cps (CO2CH2CH3) EXAMPLE 6.
N - (3' - Benzyloxynonyl) - 4,4 - dimethyl - 2 - ethoxycarbonyl - 2 - (6" - ethoxycarbonyl- n - hexyl) - pyrrolidin - 3,5 - done.
Potassium tert-butoxide (445 mg) was added in small portions over a period ot 1 hour to a refluxing solution of diethyl 2-[N-(3'-benzyloxynonyl)-N-(2"-dimethyl 2"-ethoxycarbonylpropionyl)-amino]azelate (2.3 g) in dry toluene (45 ml). The
mixture was refluxed with stirring under nitrogen for a further 45 minutes.
The solvent was evaporated in vacuo and the residue taken up in diethyl ether.
The ethereal solution was washed with dilute hydrochloride acid, sodium
carbonate solution and with water, dried over magnesium sulphate and evaporated
in vacuo to give a yellow oil (1.38 g).
The crude product was combined with that from a similar experiment (2.13 g
total) and purified by column chromatography to give N-(3 '-benzyloxynonyl)-4,4- dimethyl-2-ethaxycarbanyl-2-(6 "-ethaxycarbanylhexyl)-pyrralidin-3,5-dione as an
almost colourless oil (1.03 g).
I.R. spectrumcarbonyl absorptions at 1760 cm-1, 1730 cm-1 and 1690 cm-1.
EXAMPLE 7.
4,4 - Dimethyl - 2 - ethoxycarbonyl - 2 - 6' - ethoxycarbonylhexyll - N - 3 " - hydraxy- nonyl) - pyrrolidin - 3,5 - done.
10% Pd/C (220 mg) was added to a solution of N-(3'-benzyloxynonyl)-4,4dimethyl-2-ethoxycarbonyl-2-(6''-ethoxycarbonylhexyl)-pyrrolidin-3 ,5 -dion (450 mg) in ethanol (50 ml). The mixture was hydrogenated at 50 psi and 50" overnight.
The catalyst was filtered off and the filtrate evaporated in vacuo to give a colourless oil (390 mg).
The crude product was combined with that from a similar experiment (799 mg) total. Column chromatography of this material allowed the two diastereoisomers of 4,4-dimethyl-2-ethaxycarbanyl-2-(6'-ethaxycarbanylhexyl)-N-(3 "- hydroxynonyl)-pyrrolidin-3,5-dione to be largely separated as pale yellow oils (350 mg
and 235 mg respectively).
Both diastereoisomers gave carbonyl absorptions at 1760 cm-', 1730 cm-' and
1685 cam~' and a broad OH absorption around 3400 cm-1 in the I.R. spectrum.
EXAMPLE 8.
1 - (3' - Hydroxy - 3 ' - methylnonyl) - 2 - (6" - methoxycarbonylhexyl) -2,4,4- trimethyl
pyrrolidin - 3,5 - done.
A solution of 1 -(3 '-hydroxy-3'-methylnonyl)-2-(6"-methoxycarbonylhexyl)- pyrrolidin-3,5-dione (2.1 g) in dry dimethylformamide (10 ml) was added to a slurry of sodium hydride (640 mg, 80% dispersion) in dry benzene (10 ml) and dry dimethylformamide (10 ml). The mixture was stirred for 2 hours under nitrogen at room temperature.
A solution of methyl iodide (5 g) in dry dimethylformamide (5 ml) was run in dropwise and stirring was continued for 2 hours. Methyl iodide (5 g) was added and the mixture stirred for a further hour.
A few drops of glacial acetic acid were added and the solvent was removed in vacua. The residue was taken up in diethyl ether and the ethereal solution was washed with water, dried over magnesium sulphate and evaporated to give a yellow oil. The product was purified by column chromatography to give l - (3' - hydroxy- 3' - methylnonyl) - 2 - (6" - methoxyearbonylhexyl) - 2.4,4 - trimethylpyrrolidin - 3,5 dione as a yellow oil (453 mg, 20% yield).
Analysis: C25H45NO5 requires: C, 68.30%: H, 10.32 4; N, 3.19%.
found: C, 67.95%; H, 10.07%; N, 3.30%.
EXAMPLE 9.
2 - (6' - Carboxyhexyl) - I - (3" - hydroxy - 3" - methylnonyl) - 2,4.4 - trimethyl
pyrrolidin - 3,5 - diane.
A 10% solution of potassium carbonate (10 ml) was added to a solution of I - (3' - hydroxy - 3' - methyl - n - nonyl) - 2 - (6" - methoxycarbonyl - n - hexyl) - 2,4,4 - trimethyl - pyrrolidin - 3,5 - dione (1.35 g) in ethanol (25 ml). The mixture was gently refluxed for 24 hours.
The solvent was evaporated in vacuo and the residue was taken up in water.
The aqueous solution was extracted with diethyl ether and acidified with dilute hydrochloric acid. The acid solution was extracted with diethyl ether.and this ethereal solution was washed with water, dried over magnesium sulphate and evaporated in vacuo to give a thick, pale yellow oil. The product was purified by column chromatography to give 2-6'-carboxyhexyl)-1-(3 "-hvdraxy-3 "-methylnonyl)- 2,4,4-trimethylpyrrolidin-3,5-dione as a colourless oil (646 mg, 5 1Oo yield).
I.R. spectrum-carbonyl absorptions at 1760 cm-1, 1720 cm-1 and 1665 cm~'.
broad OH absorption around 3400 cm~'.
PHARMACOLOGICAL DATA.
Anti-secretory activity.
The anti-secretory activity of the compounds was determined by their inhibition of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach preparation (Ghosh and Schild preparation).
4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methylnonyl) - pyrrolidin - 3,5 - dione inhibited acid secretion at 500,ug/kg intravenously.
Bronchodilation activity.
The compounds were examined for their ability to inhibit 5-hydroxytryptamine-induced bronchoconstriction in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation).
4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methyl nonyl) - pyrrolidin - 3,5 - dione inhibited bronchoconstriction with an IC50 of approximately 10 ,ug/kg, intravenously.
The compounds were examined for their ability to protect conscious guinea pigs from an aerosol administered histamine challenge. The compounds were given 30 minutes before the animals were challenged with a continuous aerosol of histamine.
2 - (6' - Carboxyhexyl) - 4,4 - dimethyl - I - (3" - hydroxy - 3" - methylnonyl) - pyrrolidin - 3,5 - dione significantly prolonged the time taken to elicit a pre-convulsive cough in test animals compared with control animals when given at 2.5 mg/kg, intra-peritoneally, or when given at 10 mg/kg orally.
Toxicity.
No toxic symptoms were observed when 4,4-dimethyl-2-(6'-ethoxycarbonylhexyl)-l-(3"-hydroxy-3"-methylnonyl)-pyrrolidin-3,5-dione was dosed up to 900 mg/kg, subcutaneously, in mice.
WHAT WE CLAIM IS:
1. A compound of formula (I):
wherein: n is 4 to 8;
X is CO, protected CO or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected;
R, is hydrogen, or CO2R, represents an ester group in which the R, radical contains from I to 12 carbon atoms; RR is hydroxy or protected hydroxy;
R2 and R4 are separately hydrogen, C19 alkyl, C58 cycloalkyl, C,-8 cycloalkyl-C1~6 alkyl, phenyl, phenyl-C,~6 alkyl, naphthyl, naphthyl-C,~8 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C18 alkoxy or nitro groups: or R2 and Rd taken with the carbon atom to which they are joined represent C,-8 cycloalkyl;
A is hydrogen or a group CO2B wherein B is hydrogen, or CO2B represents an ester group in which B contains from I to 12 carbon atoms; or methyl; or a salt thereof
2. A compound according to Claim 1 , wherein X is CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R2 is hydrogen, C14 alkyl or phenyl; R4 is hydrogen, C19 alkyl. phenyl. phenyl-C1 4 alkyl, naphthyl. naphthyl-C14 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms or trifluoromethyl, C16 alkyl. C1~6 alkoxy or nitro groups; and A is hydrogen or a group CO2B wherein B is hydrogen,
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (42)
- **WARNING** start of CLMS field may overlap end of DESC **.ethereal solution was washed with water, dried over magnesium sulphate and evaporated in vacuo to give a thick, pale yellow oil. The product was purified by column chromatography to give 2-6'-carboxyhexyl)-1-(3 "-hvdraxy-3 "-methylnonyl)- 2,4,4-trimethylpyrrolidin-3,5-dione as a colourless oil (646 mg, 5 1Oo yield).I.R. spectrum-carbonyl absorptions at 1760 cm-1, 1720 cm-1 and 1665 cm~'.broad OH absorption around 3400 cm~'.PHARMACOLOGICAL DATA.Anti-secretory activity.The anti-secretory activity of the compounds was determined by their inhibition of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach preparation (Ghosh and Schild preparation).4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methylnonyl) - pyrrolidin - 3,5 - dione inhibited acid secretion at 500,ug/kg intravenously.Bronchodilation activity.The compounds were examined for their ability to inhibit 5-hydroxytryptamine-induced bronchoconstriction in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation).4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - 1 - (3" - hydroxy - 3" - methyl nonyl) - pyrrolidin - 3,5 - dione inhibited bronchoconstriction with an IC50 of approximately 10 ,ug/kg, intravenously.The compounds were examined for their ability to protect conscious guinea pigs from an aerosol administered histamine challenge. The compounds were given 30 minutes before the animals were challenged with a continuous aerosol of histamine.
- 2 - (6' - Carboxyhexyl) - 4,4 - dimethyl - I - (3" - hydroxy - 3" - methylnonyl) - pyrrolidin - 3,5 - dione significantly prolonged the time taken to elicit a pre-convulsive cough in test animals compared with control animals when given at 2.5 mg/kg, intra-peritoneally, or when given at 10 mg/kg orally.Toxicity.No toxic symptoms were observed when 4,4-dimethyl-2-(6'-ethoxycarbonylhexyl)-l-(3"-hydroxy-3"-methylnonyl)-pyrrolidin-3,5-dione was dosed up to 900 mg/kg, subcutaneously, in mice.WHAT WE CLAIM IS: 1. A compound of formula (I):wherein: n is 4 to 8; X is CO, protected CO or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R, is hydrogen, or CO2R, represents an ester group in which the R, radical contains from I to 12 carbon atoms; RR is hydroxy or protected hydroxy; R2 and R4 are separately hydrogen, C19 alkyl, C58 cycloalkyl, C,-8 cycloalkyl-C1~6 alkyl, phenyl, phenyl-C,~6 alkyl, naphthyl, naphthyl-C,~8 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C18 alkoxy or nitro groups: or R2 and Rd taken with the carbon atom to which they are joined represent C,-8 cycloalkyl; A is hydrogen or a group CO2B wherein B is hydrogen, or CO2B represents an ester group in which B contains from I to 12 carbon atoms; or methyl; or a salt thereof 2. A compound according to Claim 1 , wherein X is CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R2 is hydrogen, C14 alkyl or phenyl; R4 is hydrogen, C19 alkyl. phenyl. phenyl-C1 4 alkyl, naphthyl. naphthyl-C14 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms or trifluoromethyl, C16 alkyl. C1~6 alkoxy or nitro groups; and A is hydrogen or a group CO2B wherein B is hydrogen,or CO2B represents an ester group in which B contains from I to 12 carbon atoms: or a salt thereof.
- 3. A compound according to Claim I or 2, wherein n is 6.
- 4. A compound according to Claim 1, 2 or 3, wherein X is CO. protected CO, CHOH or C(CH3)OH.
- 5. A compound according to any one of the Claims 1 to 4, wherein R, is hydrogen or a C14 alkyl group.
- 6. A compound according to any one of the Claims 1 to 5, wherein R2 is hydrogen, C14 alkyl or phenyl.
- 7. A compound according to any one of the Claims 1 to 6, wherein R3 is hydroxy.
- 8. A compound according to any one of the Claims 1 to 7, wherein R4 is a C49 alkyl group.
- 9. A compound according to any one of the Claims 1 to 7, wherein R4 is phenyl or a phenyl-C1-6 alkyl group either of which phenyl groups may be substituted by a halogen atom or a trifluoromethyl, C18 alkyl, C16 alkoxy or nitro group.
- 10. A compound according to any one of the preceding Claims, wherein A is hydrogen.
- 11. A compound according to Claim 1, of the formula (II):wherein: p is 6 or 8; X' is CO, CHOH or C(CH3)OH; R11 is hydrogen or C,, alkyl; R'2 is hydrogen, methyl or ethyl; R', is hydrogen or C1g alkyl; and A1 is hydrogen or a group CO2Rr,; or a salt thereof.
- 12. A compound according to Claim 11, wherein p is 6.
- 13. A compound according to Claim 11 or 12, wherein X' is CO.
- 14. A compound according to Claim 11, 12 or 13, wherein R'2 is methyl.
- 15. A compound according to Claim 11, 12, 13 or 14, wherein R'4 is n-pentyl, nhexyl or n-heptyl.
- 16. A compound according to Claim 15, wherein R'4 is n-hexyl.
- 17. A compound according to Claim 11, 12, 13 or 14, wherein R'4 is a group CH(CH3)R15 or C(CH3)2R15 wherein R'5 is n-butyl, n-pentyl or n-hexyl.
- 18. A compound according to any one of the Claims 11 to 17, wherein A' is hydrogen.
- 19. A compound according to Claim 1, of the formula (III):wherein: p, X', R11, R'2 and A' are as defined in Claim I 1; and R24 is a group of formula (IV):wherein U is a bond. or a C16 alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and W, Y and Z are each hydrogen, fluorine, chlorine or bromine atoms, or CF3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; or a salt thereof.
- 20. A compound according to Claim 19, wherein p is 6.
- 21. A compound according to Claim 19 or 20, wherein X' is CO.
- 22. A compound according to Claim 19, 20 or 21, wherein R12 is methyl.
- 23. A compound according to any one of the Claims 19 to 22, wherein A' is hydrogen.
- 24. A compound according to any one of the preceding Claims, wherein W and Y are hydrogen.
- 25. A compound according to any one of the Claims 19 to 24, wherein U is a group CH2)q wherein q is O to 4.
- 26. A compound according to Claim 1, of the formula (V):wherein p, R11, R'2 and A' are as defined in Claim Il; and R34 is a group of formula (VI):wherein U, W, Y and Z are as defined in Claim 19; or a salt thereof.
- 27. A compound according to Claim 26, wherein U is a group HCH2)q wherein q is O to 4.
- 28. A compound according to any one of the Claims ii to 27, but wherein R12 is defined as a phenyl group.
- 29. A compound according to any one of Claims 11 to 28, but wherein A' is defined as a methyl group.
- 30. A compound according to Claim 1, of the formula (VII):wherein: p, X1, R', and R'2 are as defined in Claim 11; A" is hydrogen, or a group CO2R11, or methyl: R84 is a group of formula (VIII):wherein U is as defined in Claim 19 and r is O to 3; or a salt thereof.
- 31. A compound according to Claim 30, wherein U is a group ACH2)q wherein q is O to 6.
- 32. A compound according to Claim 1, of the formula (IX):wherein: p, X', R' and A" are as defined in Claim 30; Rb2 and Rb4 are separately C59 alkyl or groups of formula (IV), (VI) or (VIII) as defined in Claims 19, 26 and 30 respectively; or Rb2 and Rb4 taken together with the carbon atom to which they are joined represent C58 cycloalkyl; or a salt thereof.
- 33. A compound according to any one of the Claims 11 to 32, but wherein X' is defined as a protected carbonyl group.
- 34. A pharmaceutical composition comprising a compound according to any one of the Claims I to 33 and a pharmaceutically acceptable carrier.
- 35. A process for the preparation of a compound according to Claim 1, which process comprises either: (i) the mono-methylation of a compound of the formula (X):wherein A is hydrogen or CO2B to yield a corresponding compound of the formula (I) wherein A is hydrogen or CO2B; (ii) the cyclisation of a compound of the formula (XIII):wherein R8 contains from I to 12 carbon atoms, to yield a compound of the formula (I) wherein A is CO2B; or (iii) the methylation of a compound of the formula (I) wherein x is CO and A is hydrogen to yield the corresponding compound wherein A is methyl; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C,, alkyl Grignard reagent or C14 alkyl metallic complex when R is C14 alkyl, and then optionally protecting the CROH hydroxy group.
- 36. A process according to Claim 35, wherein a compound of the formula (I) wherein A is hydrogen or methyl is prepared by the di- or tri- methylation of a compound of the formula (XI):
- 37. '37. A compound according to Claim 1, substantially as hereinbefore described with reference to any one of the Examples I to 3 and 6 to 9.
- 38. A process according to Claim 35 or 36. substantially as hereinbefore described with reference to any one of the Examples I to 3 and 6 to 9.
- 39. A compound according to Claim 1. whenever prepared by a process according to any one of the Claims 35, 36 or 38.
- 40. A method of treatment or prophylaxis of disorders in domestic animals, which method comprises the administration of an effective amount of a compound according to Claim 1.
- 41. 4,4 - Dimethyl - 2 - (6' - ethoxycarbonylhexyl) - I - (3" - hydroxy - 3"methylnonyl) - pyrrolidin - 3,5 - dione.
- 42. 2 - (6' - Carboxyhexyl) - 4,4 - dimethyl - I - (3" - hydroxy - 3" - methylnonyl) - pyrrolidin - 3,5 - dione.
Priority Applications (22)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB43989/75A GB1560942A (en) | 1975-10-25 | 1975-10-25 | 10,10,-dimethyl-12-azaprostaglandins |
| NZ182263A NZ182263A (en) | 1975-10-25 | 1976-10-07 | 2-carboxyalkyl-4,4-dimethyl-1-hydroxy-alkyl-pyrrolidin-3,5-dione derivativesand pharmaceutical compositions |
| IL50643A IL50643A (en) | 1975-10-25 | 1976-10-08 | 12-aza-11/oxo-9,9-dimethyl-15-hydroxy-prostanoic acid analogues their preparation and pharmaceutical compositions containing them |
| AU18687/76A AU506442B2 (en) | 1975-10-25 | 1976-10-14 | Prostaglandin analogues and pharmaceutical compositions |
| ZA766179A ZA766179B (en) | 1975-10-25 | 1976-10-15 | Methylated cyclic amides |
| US05/732,989 US4136190A (en) | 1975-10-25 | 1976-10-15 | 4,4-dimethyl-3,5-pyrrolidinediones |
| NO763566A NO763566L (en) | 1975-10-25 | 1976-10-19 | |
| FI762999A FI762999A (en) | 1975-10-25 | 1976-10-20 | |
| FR7631526A FR2328465A1 (en) | 1975-10-25 | 1976-10-20 | METHYL CYCLIC AMIDES |
| AT0788676A AT364820B (en) | 1975-10-25 | 1976-10-22 | METHOD FOR PRODUCING NEW METHYL-SUBSTITUTED CYCLIC AMIDES |
| ES452648A ES452648A1 (en) | 1975-10-25 | 1976-10-22 | 4,4-dimethyl-3,5-pyrrolidinediones |
| SE7611774A SE417091B (en) | 1975-10-25 | 1976-10-22 | PROCEDURE FOR PREPARING PHARMACOLOGICALLY ACTIVE DERIVATIVES OF 2-CARBOXIALKYL-4,4DIMETHYL-PYRROLIDIN-5-ON |
| CA263,954A CA1068716A (en) | 1975-10-25 | 1976-10-22 | Methylated cyclic amides |
| IE2329/76A IE44299B1 (en) | 1975-10-25 | 1976-10-22 | 10,10-dimethyl-12-azaprostaglandins |
| BE171761A BE847594A (en) | 1975-10-25 | 1976-10-22 | METHYL CYCLIC AMIDES, |
| NL7611760A NL7611760A (en) | 1975-10-25 | 1976-10-22 | PROCEDURE FOR PREPARING NEW SUBSTITUTED CYCLICAL AMIDES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. |
| HU76BE1276A HU174538B (en) | 1975-10-25 | 1976-10-22 | Process for producing 4,4-dimethyl-pyrrolidine-3,5-dion derivatives |
| DK479076A DK479076A (en) | 1975-10-25 | 1976-10-22 | PROCEDURE FOR MAKING CYCLIC AMIDES |
| DE19762647968 DE2647968A1 (en) | 1975-10-25 | 1976-10-22 | METHYL-SUBSTITUTED CYCLIC AMIDES, THE METHOD FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS |
| JP51127730A JPS5253856A (en) | 1975-10-25 | 1976-10-23 | Production of prostaglandine like compound and pharmaceutical composition |
| ES462849A ES462849A1 (en) | 1975-10-25 | 1977-10-01 | 4,4-dimethyl-3,5-pyrrolidinediones |
| US05/954,188 US4187312A (en) | 1975-10-25 | 1978-10-24 | 3-Hydroxy-4,4-dimethyl-5-pyrrolidone derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB43989/75A GB1560942A (en) | 1975-10-25 | 1975-10-25 | 10,10,-dimethyl-12-azaprostaglandins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1560942A true GB1560942A (en) | 1980-02-13 |
Family
ID=10431271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB43989/75A Expired GB1560942A (en) | 1975-10-25 | 1975-10-25 | 10,10,-dimethyl-12-azaprostaglandins |
Country Status (3)
| Country | Link |
|---|---|
| BE (1) | BE847594A (en) |
| GB (1) | GB1560942A (en) |
| ZA (1) | ZA766179B (en) |
-
1975
- 1975-10-25 GB GB43989/75A patent/GB1560942A/en not_active Expired
-
1976
- 1976-10-15 ZA ZA766179A patent/ZA766179B/en unknown
- 1976-10-22 BE BE171761A patent/BE847594A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA766179B (en) | 1977-09-28 |
| BE847594A (en) | 1977-04-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |