GB2130575A - Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins - Google Patents
Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins Download PDFInfo
- Publication number
- GB2130575A GB2130575A GB08231938A GB8231938A GB2130575A GB 2130575 A GB2130575 A GB 2130575A GB 08231938 A GB08231938 A GB 08231938A GB 8231938 A GB8231938 A GB 8231938A GB 2130575 A GB2130575 A GB 2130575A
- Authority
- GB
- United Kingdom
- Prior art keywords
- prost
- alpha
- ynoic acid
- cyclohexyl
- amide
- 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.)
- Granted
Links
- 150000001408 amides Chemical class 0.000 title claims description 159
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 20
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 9
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 354
- -1 piperidino, piperazinyl Chemical group 0.000 claims description 119
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 95
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 4
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 206010055690 Foetal death Diseases 0.000 claims description 2
- 206010061459 Gastrointestinal ulcer Diseases 0.000 claims description 2
- 208000025865 Ulcer Diseases 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000035558 fertility Effects 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 230000035876 healing Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 claims description 2
- 238000007910 systemic administration Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 231100000397 ulcer Toxicity 0.000 claims description 2
- HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 claims 1
- 101100162200 Aspergillus parasiticus (strain ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1) aflD gene Proteins 0.000 claims 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- LXWHOYSOMNNXRS-UHFFFAOYSA-N pyrazolidine-1-carboxamide Chemical compound NC(=O)N1CCCN1 LXWHOYSOMNNXRS-UHFFFAOYSA-N 0.000 description 57
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 7
- 229960004132 diethyl ether Drugs 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
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- 229940093499 ethyl acetate Drugs 0.000 description 5
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- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
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- 238000009472 formulation Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
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- 150000007513 acids Chemical class 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
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- 239000002585 base Substances 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
New prostaglandin derivatives in optically active or racemic form having formula <IMAGE> wherein each of R' and R'' represents, independently, hydrogen, C1-C6 alkyl, aryl or heterocyclyl or R' and R'', taken together with the nitrogen atom to which they are linked, form a heterocyclic ring; the symbol represents a single or a double bond, wherein: a) when the symbol --- is a double bond, R1 is a hydrogen atom and R2 and R3, taken together, form an oxo group; b) when the symbol --- is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or acyloxy or R2 and R3, taken together, form an oxo group; one of R4 and R5 is hydroxy and the other is hydrogen; each of R6 and R7 represents, independently, hydrogen, C1-C4 alkyl or fluorine; n is zero, 1, 2 or 3; R8 represents a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from a') halogen b') trihalo-C1-C6-alkyl; c') C1-C4 alkyl; d') C1-C4 alkoxy; e') phenyl; and f') phenoxy; and the pharmaceutically or veterinarily acceptable salts thereof.
Description
SPECIFICATION
Amide derivatives of 13,14-didehydro-cycloalkyl-prostaglandins The present invention relates to am ides of 13,1 4-didehydro-cycloalkyl-prostaglandins, to a process for their preparation, to pharmaceutical and veterinary compositions containing them and to certain intermediates useful for their preparation.
The invention provides optically active or racemic prostaglandin derivatives of formula (I)
wherein
each of R' and R" represents, independently, hydrogen, C1-Cs alkyl, aryl or heterocyclyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring;
the symbol ---- represents a single or a double bond, wherein::
a) when the symbol ---- is a double bond, R1 is a hydrogen atom and R2 and R3, taken together, form an oxo group;
b) when the symbol ---- is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or acyloxy or
R2 and R3, taken together, form an oxo group;
one of R4 and R5 is hydroxy and the other is hydrogen;
each of R6 and R7 represents, independently, hydrogen, C1 -C4 alkyl or fluorine;
n is zero, 1,2 or3; Re represents a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from a') halogen; b') trihalo-C1-C6-alkyl; c') C1-C4 alkyl; d') C1-C4 alkoxy; e') phenyl; and f') phenoxy; and the pharmaceutically or veterinarily acceptable salts thereof.
The compounds and salts of the present invention have the advantage that they possess greater activity when administered orally than related compounds disclosed in the prior art, in particular those specifically disclosed in British published Application No. 2009145A. This greater activity is made possible by their better gastrointestinal absorption.
The formula reported above for the compounds covered by this invention includes all possible isomers, in particular stereoisomers, as well as their mixtures, for example mixtures of epimers. The double bond in 5 (6) is a cis double bond. In the formulae of this invention, dashed lines (l l l l l l ll l) indicate that the substituents are in the a-configuration, that is, beneath the plane of the ring or of a side chain.
Wedges () indicate that the substituents are in the ss-configuration, that is, above the plane of the ring, or of a side chain. Wavy lines ( 0 ) indicate that the substituents, when the carbon atom to which they are bound is asymmetric, may be either in the a- or ss-configuration or in the (a,ss)-configuration, that is a mixture of the two epimers. For example, the hydroxy group bound to the carbon atom in position 15 may be in the configuration ((Y), (ss) and (a,ss), that is, a mixture of the 15(a)-and 1 5(ss)-epimers.
In the same way, when the carbon atom in position 16 has two different substituents, these may be 16(a), 16(P) and 1 6((x,ss), that is a mixture of the two 16(a)-and 1 6(ss)-epimers. The symbol S or R of each chiral centre is assigned according to the sequence rule arranging the ligands in order of decreasing atomic number.
The alkyl, alkoxy and trihaloalkyl groups can be straight or branched chains.
A halogen atom is preferably fluorine, chlorine or bromine.
When one or both of R' and R" are C1-C6 alkyl, they are preferably methyl, ethyl, propyl or butyl.
When one or both of R' and Rare aryl, they are preferably phenyl.
When one or both of R' and R", are heterocyclic, the heterocyclic group is preferably chosen from pyrrolyl, pyrazoly, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl and pyrazolidinyl.
When R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring, the heterocyclic ring is preferably chosen from: pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl, morpholino and pyrazolidinyl. R' and R" as individual heterocyclic groups can also be piperidino or morpholino.
When R3 is acyloxy, this is preferably a benzoyloxy group or a C2-Ce alkanoyloxy group, for example, acetoxy or propionyloxy.
When one or both of Re and R7 are C1 -C4 alkyl, they are preferably methyl or ethyl.
When R8 is a C3-C7 cycloalkyl group optionally substituted as described above under points a') to f'), it is preferably a group chosen from cyclopentyl, cyclohexyl and cycloheptyl. Preferred compounds of the invention are the compounds of formula (I), wherein:
R' and R" are, independently, hydrogen or C1-C4 alkyl; or
R' and R", taken together with the nitrogen atom to which they are linked, form a pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl or morpholino ring;
the symbol ~~~~ is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or acyloxy or R2 and R3, taken together, form an oxo group; Re represents a radical chosen from cyclopentyl, cyclohexyl and cycloheptyl, each of them being unsubstituted or substituted by one or more a') halogen, b') trihalo-C1-Ce-alkyl, c') C1-C4 alkyl, d') C1 -C4 alkoxy, e') phenyl, f') phenoxy; R4, R5, R6, R7 and n are as defined above and the pharmaceutically or veterinarily acceptable salts thereof.
Particularly preferred compounds of the invention are the compounds of formula (I), wherein
R' and R" are, independently, hydrogen or methyl; or R' and R", taken together with the nitrogen atom to which they are linked, form a piperidino or morpholino ring;
the symbol = is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or R2 and R3, taken together, form an oxo group;
each of Re and R7 represents, independently, hydrogen, methyl or fluorine;
R4, R5 and n are as defined above; R5 is cyclopentyl or cyclohexyl; and the pharmaceutically or veterinarily acceptable salts thereof.
As stated above, this invention also covers pharmaceutically orveterinarily acceptable salts of these compounds.
Examples of particularly preferred salts of the compounds of formula (I) include acid addition salts with inorganic acids, e.g. nitric, hydrochloric, hydrobromic, hydroiodic, sulphuric, perchloric and phosphoric acid, or with organic acids, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, fumaric, cinnamic, mandelic, salicylic acid, and with organic-sulphonic acids, e.g. methanesulphonic, p-toluene-sulphonic and cyclohexyl-sulphonic acid.
Examples of preferred compounds according to this invention are: 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclophentyl-prost-5-en-13-ynoic acid amide:: 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid admide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(R)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α;,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α-11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9a,1 1α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide;; 5c,9a,1 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclopentyl-prost-5-en-1 3-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-sluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide;; 5c-9α,11α,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9a,1 1 a,1 5(S)4rihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 3-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9or,l 1 α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α ;,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic-acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic-acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9a,1 1α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c,9a,l 1 a,1 5(S)4rihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide;
5c-9a,1 1 a,1 5(R,S)-trihyd roxy-1 6(S)-fluoro-1 6-methyl-I 8,1 9,20-tri nor-l 7-cycl ohexyl-prost-5-en-l 3-ynoic acid N,N-dimethyl-amide; 5c-9a,l 1 a,1 5(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9-oxo-11α;,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-l 1 a,1 5(S)-dihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide;; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α;,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-l 1 a,1 5(R)-dihydroxy-1 6(S)-fluoro-l 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-llu,l S(R,S)-dihydroxy-16(S)-fluoro-17,1 8,19,20-tetranor-1 6-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide;; 5c-9-oxo-1 1 a,l 5(R,S)-dihydrnxy-l 6(S)4luoro-l 6-methyl-1 8,1 9,204rinor-l 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyul-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α;,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-1 1 a,1 5(S)-dihydroxy-l 8,1 9,20-trinor-l 7-cyclopentyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide;;
5c-9-oxo-11 a,lS(R)-dihydroxy-l G(S)-fluoro-18,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-l 3-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-1 1 a,l 5(R,S)-dihydroxy-1 6(S)4luoro-1 8-1 9-20-trinor-17-cyclohexyl-prost-5-en-1 3-ynoic acid N,Ndimethyl-amide;
5c-9-oxo-1 1 a,l 5(R)-dihydroxy-1 6(S)4luoro-1 8,1 9,20-trinor-l 7-cyclopentyl-prost-5-en-l 3-ynoic acid N,Ndimethyl-amide; Sc-9-oxo-l 1 a,1 5(R,S)-dihydroxy-l 6(S)4luoro-1 8,1 9,20-trinor-l 7-cyclopentyl-prost-5-en-1 3-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide;; Sc-9-oxo-l 1 a,1 5(R)-dihydroxy-l 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prnst-5-en-l 3-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α;,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-1 1 α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α;,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(R,S)dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-1 1 α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α;,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α ;,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trino-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; Sc-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(S)4luoro-1 6-methyl-l 8,1 9,204rinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid morpholin-amide; and 5c-9-oxo-1 1 a,l 5(R,S)-di hyd roxy-l 6(R)4l uoro-1 6-methyl-1 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide.
Where in the above list of compounds and hereafter in the Examples and claims reference is made to "morpholin-amide", "piperidin-amide", "piperazine-amide" and "pyrazolidin-amide", these terms are intended to cover amide groups where the nitrogen atom of the amide group is a ring nitrogen atom in the heterocyclic group. Thus these groups are respectively
Alternative names for these groups could be N,N-ethyleneoxyethylene amide, N,N-pentamethylene amide, N,N-ethyleneaminoethylene amide and N,N-n-propyienamino amide, respectively.
The compounds of general formula (I) can be prepared by a process comprising: a) reacting a reactive derivative of an optically active or racemic compound of formula (II)
wherein
when the symbol = represents a double bond, R'1 is a hydrogen atom and R2 and R'3, taken together, form an oxo group while when the symbol = represents a single bond, R'1 is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom, R2 is hydrogen, R'3 is hydroxy, acyloxy or a protecting group bound to the ring through an ethereal oxygen atom or R2 and R'3, taken together, form an oxo group; one of R'4 and R'5 is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and Re, R7, n and Re are as defined above, with a compound of formula (III)
wherein
R' and R" are as defined above, thus giving an optically active or racemic compound of formula (IV)
wherein
R', R", R'3, R2, R'1, R'4, R'5, Re, R7, n and Re are as defined above, and then, when necessary, removing the hydroxy protecting groups; or b) reacting an optically active or racemic compound of formula (V)
wherein
M represents -CC- or
and Xis bromine, chlorine or iodine;Z is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom; one of R'4 and R'e is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and Re, R7, n and Re are as defined above, with a Wittig reagent containing a group
wherein R' and R" are as defined above, to give an optically active or racemic compound of formula (VI)
wherein
R', R", Z, R'4, R'5, R6, R7, n and R8 are as defined above, which, when the 11-and 15-hydroxy groups are in the protected form, if desired, may be esterified to give a 9α;-acyloxy derivative of a compound of formula (Vl) and then removing the protecting groups at the 11- and/or 15-positions, if present, both in a compound of formula (VI) and in its acyloxy derivatives, thus giving a compound of formula (I), wherein R3 is hydroxy or acyloxy, R2 is hydrogen, R1 is hydroxy, the symbol = represents a single bond and R', R", R4, R5, Re, R7, n and Re are as defined above; or c) oxidizing an optically active or racemic compound of formula (VII)
wherein
Z' is a protecting group bound to the ring through an ethereal oxygen atom; one of R"4 and R"5 is a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and R',R",R6,R7, n and Re are as defined above, to give an optically active or racemic compound of formula (VIII)
wherein
R', R", Z', R"4, R"5, R6, R7, n and R8 are as defined above, which, in turn, is subjected to the removal of the ether protecting groups to give, depending on the reaction conditions, either a compound of formula (I), where = is a single bond, R1 is hydroxy, R2 and R3, taken together, form an oxo group and R', R", R4, Rs, Re, R7, n and Re are as defined above or a compound of formula (I), where ---- is a double bond, R1 is hydrogen,
R2 and R3, taken together, form an oxo group and R', R", R4, Rg, Re, R7, n and Re are as defined above; and/or, if desired, salifying a compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof, and/or, if desired, resolving a mixture of isomers into the single isomers.
A protecting group bound to the ring orto the chain through an ethereal oxygen atom, i.e. an ether group, should be easily convertible to a hydroxy group under mild reaction conditions, e.g. acid hydrolysis.
Examples are acetalic ethers, enol-ethers and silyl-ethers. The preferred are
Wherein G is -O- or -CH2- and Alk represents a lower, e.g. C1-C4, alkyl group.
The reaction conditions to be used in the reaction between a reactive derivative of a compound of formula (II) and an amine of formula (III) depend, in particular, on the kind of the reagents used.
A reactive derivative of a compound of formula (II) may be, for example, a reactive ester, e.g. a Ci-Ce alkyl ester; an acyl halide, e.g. chloride or bromide; an anhydride; a mixed anhydride; an azide; or a salt, for instance a salt formed with alkali metals or alkaline earth metals.
When the reactive derivative of a compound of formula (II) is a reactive ester thereof and the compound of formula (Ill) is ammonia, the reaction may be carried out by using gaseous ammonia at a temperature ranging from about 5"C to about 40"C, preferably from 15"C to 25"C; while, when a compound of formula (III) is an amine, the reaction may be carried out, preferably, in an inert solvent, e.g. benzene, toluene, at temperatures ranging from room temperature to the reflux temperature.
When a reactive derivative of a compound of formula (II) is an acyl halide, e.g. the acyl chloride, the reaction with ammonia or a suitable amine of formula (III) may be carried out in an inert solvent, e.g. benzene ortoluene, or in an aqueous solvent, in this case in the presence of an inorganic base, e.g. NaHCO3 or
Na2CO3, as acid acceptor. When in the lactol of formula (V) M is -C=C- or CH=CX- in which X is bromine or iodine, the Wittig reaction may be carried out using about 1 up to 4 moles, preferably 2, of Wittig reagent per mole of lactol and the reaction may last from about 10-20 minutes to several hours, depending on the temperature and on the concentration of the reacting mixture and on the Wittig reagent used.When in the lactol of formula (V) M is -CH=CX-, in which Xis chlorine, it is necessary, by using, for example, 1.5 to 2.5 moles of Wittig reagent per mole of lactol, to prolong the reaction time up to ten hours, or, if it is desired to use shorter reaction times, it is necessary to employ a great excess of Wittig reagent; at least 5 moles of
Wittig reagent per mole of lactol, for reaction times of about 30 minutes. Therefore, when in the lactol of formula (V) M is -CH=CX-, Xis preferably bromine or iodine.
When in the lactol of formula (V) M is -CH=CX-, wherein Xis bromine, chlorine or iodine, the hydrogen atom linked to the carbon atom in the 13-position and the halogen atom linked to the carbon atom in the 14-position may be either in the trans-position, i.e. geometric trans-isomers, or in the cis-position, i.e.
geometric cis-isomers. Preferably they are in the trans-position. The Wittig reaction is performed by using the conditions usually followed for this kind of reaction, i.e. in an organic solvent, for example diethylether, hexane, dimethylsulphoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium tert.butoxide, at temperatures from about 0 C to the reflux temperature of the reaction mixture, preferably at room temperature or below.
The term "Wittig reagent" includes compounds of general formula
where Q represents aryl, i.e. phenyl, or Ci-Ce alkyl, i.e. ethyl; Hal is halogen, e.g. bromine or chlorine and R' and R" are as defined above.
The preparation of the Wittig reagent is discussed in detail byTrippett, Quart. Rev.: (1963) XVII, No. 4,406.
When in the lactol of formula (V) M is -CH=CX-, wherein Xis as defined above, during the reaction with the Wittig reagent, the dehydrohalogenation takes place as easily when the hydrogen atom linked to the carbon atom in the 13-position and the halogen atom linked to the carbon atom in the 14-position are in the trans-position as when they are in the cis-position. The optional acylation of the 9a-hydroxy group in a compound of formula (VI) to afford the respective 9a-acyloxy derivative may be performed in a conventional way, for example by treatment with an anhydride or a halide, e.g. a chloride of a carboxylic acid in presence of a base.
The oxidation of the 9a-hydroxy group in a compound of formula (VII) to yield the respective 9-oxo derivative may be carried out through, for example, Jones reagent (G.I. Poos and all. Am. Soc. 75,422, 1953) or Moffatt reagent (Am. Soc. 87, 5661, 1965).
The removal of the known protecting groups bound to the ring, or respectively to the chain, by an ethereal oxygen atom, for example in a compound of formula (IV) or in a compound of formula (VI) or in its 9a-acyloxy derivatives, is, whenever required, performed under conditions of mild acid hydrolysis, for example with a mono- or polycarboxylic acid, e.g. formic, acetic, oxalic, citric and tartaric acid, and in a solvent, which may be, for example, water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols and mixture of them or with a sulfonic acid, e.g. p-toluene-sulfonic acid, in a solvent, such as a lower aliphatic alcohol, e.g. in methanol or in ethanol or with a polystyrene sulphonic resin.For example a solution of 0.1 to 0.25 N poly-carboxylic acid, in water e.g. oxalic or citric acid, is used in the presence of a suitable low boiling co-solvent which is miscible with water and which can be easily removed in vacuo at the end of the reaction. As discussed previously, removal of the protecting groups in compounds of formula (VIII) may give, depending on the reaction conditions, either a compound of formula (I) where the symbol = is a single bond, R1 is hydroxy and R2 and R3 together form an oxo group, or one in which - is a double bond, R1 is hydrogen and R2 and R3 together form an oxo group.The first may be prepared as the sole reaction product by running the reaction between 1 5"C and 40"C, while at higher temperatures, for instances, for several hours at reflux, only the second is obtained.
The separation of a mixture of isomers into the single isomers may be carried out by conventional methods. For example the separation of a mixture of epimers, e.g. 15(S)-and 15(R)-epimers, may be carried out by fractional crystallization from a suitable solvent or by chromatography, either column chromatography or high pressure liquid chromatography.
The reactive derivative of the acids of formula (II), and the lactols of formula (V) are known compounds, e.g. as described in our published U.K. patent application No. 2009145A, or in our U.K. patent specification No. 1,483,880 or may be obtained by known methods from known compounds, e.g. from those described in the above published British patent application or British patent specification.
For example, compounds having formula (V), in which M is -C-C-, may be prepared by dehydrohalogenation of the corresponding 14-halo derivatives. Dehydrohalogenation may be carried out in an aprotic solvent preferably chosen from dimethylsulphoxide, dimethylformamide and hexamethylphosphoramide by treatment with a base preferably chosen from potassium tert-butylate, an alkali metal amide and the CH3SO-CH26 anion.
Among the reaction intermediates described above, the compound of formula (IV) is new and is another object of the present invention.
The compounds of formula (I) are encompassed by the general formula of our published U.K. Patent
Application No. 009 145A, but none of them is specifically described therein.
The compounds of formula (I) may be used on mammals in all the conditions where natural prostaglandins are indicated, and administered by the usual routes, e.g. orally, parenterally, rectally or by aerosol, with the advantages of superior resistence to the enzyme 15-prostaglandin dihydrogenase, which as is known, rapidly inactives natural prostaglandins. The new compounds are also endowed with more lasting therapeutic activity than natural prostaglandins, when administered by usual routes and expecially when administered by oral way. For example, the compounds of formula (I), and in particular the 9a-hydroxy derivatives, exhibit oxytocic action, that is, they may be used instead of oxytocic to induce labor or to expel a dead fetus in pregnant females, both in humans and in animals.In this application the compounds are administered either by intravenous infusion at a dose of approximately 0.01 ijg/kg/minute until the end of labor, or orally at a single or multiple doses from about 0.1 mg to about 5 mg per dose.
Further, the compounds of formula (I), particularly the 9hydroxy derivatives, show also luteolytic activity and therefore they may be used in fertility control with the advantage of a considerably reduced capacity to stimulate the smooth muscles. Therefore, the side effects of natural prostaglandins, like vomiting and diarrhea, are absent. The luteolytic activity of the new compounds was evaluated for example on rats. In this test, as shown in Table 1, a comparison was made between the activity of a compound of invention (R=NH2) and that of two compounds of the prior art after either oral (p.os) or subcutaneous (s.c.) administration.
TABLE 1
ED50 kg R s.c. p.os NH2 2.5 40 OCH3 3 90 OH 4 150 ED50 represents the minimal effective dose able to induce luteolytic activity on the 50% of the rat population under treatment.
Table I shows that the amide derivative is the most potent in stimulating a pharmacological response. In particular, although by s.c. administration the ED50 values are very near, it is evident that the amide derivative, when administered by oral route, is the most active. Therefore the amide shows a better gastrointestinal absorption, this is due to the different hydrophilic properties owned by the chemical groups bound at the C-i carbon of the prostaglandin derivatives. Another useful pharmacological property of the compounds of formula (I), particularly the 9-oxo derivatives, is their anti-ulcerogenic activity. In fact they are useful to reduce and control excessive gastric secretion in mammals.So, they reduce or eliminate the formation of gastrointestinal ulcers and, at the same time, are able to, accelerate the healing process of any ulcers already present in the gastrointestinal tract. The compounds offormula (I) are therefore also useful for reducing the undesirable gastrointestinal side-effects resulting from systemic administration of antiinflammatory prostaglandin synthetase inhibitors and may be, therefore, used for this purpose in association with them. The compounds of formula (I) in accordance with these purposes can be administered orally, parenterally, i.e. by intravenous injection or infusion, or by intramuscular injection, by inhalation or rectally. When administered orally the compounds of the invention may be used at a dosage ranging from about 1 mg to about 10 mg, preferably 5 mg, once or three times a day.In intravenous infusion, the dosage varies from approximately 0.01 p9 to 0.05 9 per kilogram of body weight per minute. The total daily dose, both by injection and by infusion, is on the order of 0.1 - 20 mg. Of course in the treatment of the above conditions, the exact treatment level depends on the case history of the patient to be treated.
The toxicity of the compounds of formula (I) was found to be quite neglible and therefore they can be safely used in therapy. The evaluation of the toxicity (as orientative acute toxicity, i.e. LD50), was carried out, e.g., as follows: nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed; the LD50 was assessed on the seventh day after the treatment. For example the LD50 of the compound 5c-9Os ,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycloheXyl- prost-5-en-1 3-ynoic acid amide was found > 3.000 mg/kg body weight.The compounds of formula (IV) are endowed with the same pharmacological activities of the compounds of formula (I) and are administered to humans or animals for the same therapeutic purposes, at the same dosage levels and through the same routes of administration.
The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, such as, sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
As stated above a further way of administration may be inhalation. For such use, suitable compositions may comprise a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt, in water, for administration by means of a conventional nebulizer. Alternatively, the compositions may comprise a suspension or a solution of the active ingredient in a conventional liquefied propellant, such as: dichlorodifluoromethane or dichlorotetrafluoroethane, to be administered from a pressurized container, i.e., an aerosol dispenser.
When the medicament is not soluble in the propellant, it may be necessary to add a co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate, and/or a surface-active agent to the composition, in order to suspend the medicament in the propellant medium and such surface-active agents may be any of those commonly used for this purpose, such as non-ionic surface-active agents, e.g., lecithin. Other suitable pharmaceutical form may be for example powders. The powders may be administered by means of a suitable insufflator device and in this case the fine particle sized powders of the active ingredient may be mixed with a diluent material such as lactose.
This invention is illustrated but not limited by the following examples.
The abbreviations THP, DIOX, DMSO, THF, DMF, DIBA, Et2O, and EtOH refer to tetrahydropyranyl, dioxanyl, dimethylsulphoxide, tetrahydrofuran, dimethylformamide, diisobutylaluminum hydride, diethyl ether and ethyl alcohol, respectively. All the temperature are expressed in degrees centigrade, and optical rotation measures refer to 20 C and a concentration of 1% by weight of the compound in the specific solvent.
Example 1
A solution of 5c-9a,1 1α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid methyl ester (0.5g) in methyl alcohol (10 ml) was cooled with brine and dry NH3 was bubbled into this solution until saturation.
The reaction vessel was closed and the reacting mixture was maintained at room temperature for 24 hours; then the NH3 was stripped with N2 and the alcohol was removed.
The crude product was purified with preparative chromatographic technique on silica gel using hexane/ethyl acetate == 1/1 as eluent : 0.42 g of pure 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17- cyclohexyl-prost-5-en-1 3-ynoic acid amide were collected; [α]D = + 34.8; [a]365 = + 86.1 (C=l EtOH)
By proceeding analogously the following compounds were obtained:: 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D = + 19.5; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid amide [(X]D = + 19.7; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D = + 8.8; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D = + 7.2; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D = + 13.9;; 5c-9a,l 1 α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide [OL]D = + 24.7; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide [(X]D = + 11.2; 5c-9a,1 1 α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [Of]D = + 38.7; 5c-9a,1 1α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide [a]D = + 31.0; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide: [a]0 = + 17.4; [α]365 = + 66.9 (C=l EtOH); 5c-9a,1 1α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide [Of]D= + 10.2; 5c-9a,l 1 a,1 5(S)-trihydroxy-20-nor-1 9-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α;,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9a,1 1α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yunoic aid N,N-dimethylamide; 5c-9a,1 1α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9a,1 1α ;,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9a,l 1α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid, N,Ndimethyl amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide [a]D = + 18.1; 5c-9α,11α;,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide [α]D = + 12.0; 5c-9a,1 1 α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide [a]o = + 37.6; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide [O5]D = + 37.2; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide [OL]D = + 6.5; 5c-9α,11α;,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D = + 11.2; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D = + 7.7; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-l 6(S)4luoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide [a]0 + 12.1; 5c-9a,l 1 a,l 5(R)-trihydroxy-l 6(R)4luoro-1 6-methyl-l 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide [aj = + 15.9; 5c-9a,1 1α;,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide [a]D = + 29.6; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c,9a,l 1 a,l 5(S)-trihydroxy-l 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid N,N-dlmethylamide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9a,l 1 a,l 5(R)-trihydroxy-1 6(S)-fluoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α;,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-l 9-cyclohexyl-prost-5-en-l 3-ynoic acid pyrazolidin amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,l la,l S(R,S)-trihydroxy-l 6(S)-fluoro-20-nor-l 9-cyclohexyl-prost-5-en-l 3-ynoic acid pyrazolidinamide; 5c-9a,l 1α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α;,15(S)-trihydroxy-19,0-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9a,1 1α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-54inor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-54inor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,1 1α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide;; 5c-9ol,l loc,l S(R,S)-trihydroxy-l 6(S)-fluoro-18,19,20-trinor-l 7-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,1 1α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,l 5(R,S).trihydroxy-l 6(S)-fluoro-1 8,19,1 0-trinor-1 7-cyclopentyl-prnst-5-en-1 3-ynoic acid pyrazoli- dine-amide; 5c,9a,1 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidinamide;
5c-9a,l 1 a,l 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-l 6-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidinamide;; 5c9a,1 1 a,1 5(R)-trihydroxy-l 6(S)-fluoro-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prnst-5-en-1 3-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-l 6(S)4luoro-I 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-l 6(S)4luoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexylprnst-5-en-1 3-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)-fiuorn-1 6-methyl-I 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide;
5c-9a,1 1 a,l 5(R)-trihydroxy-1 6(R)4luoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide;;
5c-9a,1 1 a,1 5(S)4rihydroxy-l 8,1 9,20-trinor-l7-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(S)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)-fluoro-20-nor-1 9-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide;; Sc-9a,1 1 a,1 5(S)-trihydroxy-l 9,20-dinor-1 8-cyclopentyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-l 6(S)4luoro-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-1 3-ynoic acid piperidinamide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(R)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 8,1 9,20-trinor-l 7-cyclopentyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,l 5(R)-trihydroxy-1 6(S)4luoro-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid piperidinamide;; 5c-9a,l 1 α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoi acid piperidinamide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide; 5c,9a,1 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-1 6(S)Jluoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(S)-fluoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 6-methyl-l 8,1 9,20-trinor-17-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(R)-fluoro-1 6-methyl-1 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide;; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9a,11 α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13k-ynoic acid morpholin-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α ;,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9a,ll 1 α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c,9a,l 1 a,1 5(S)-trihydroxy-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid morpholin-amide; 5c-9,11a,l S(S)-trihydroxy-17,18,1 9,20-tetranor-l 6-cyclopentyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-167-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9α;,11α,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9a, 11 a, 1 5(R,S)-tri hydroxy-l 6(S)-fluoro-l 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9cl,l la,l R )-tri hyd roxy- 6(R)4luoro-1 6-methyl-18,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-l 13-yn oic acid morpholin-amide; and 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperazin amide.
Example 2
A solution of potassium tert.butoxide (2.325 g) in dry DMSO (15 ml) under dry nitrogen was stirred; by cooling with water bath triphenylphosphonium pentanoic acid N,N-dimethyl-amide bromide (4.2 g) was added to the solution. The temperature of the reacting mixture was kept below 30"C and the addition was completed in about 15 minutes; then a solution of 3α,5α-dihydroxy-2ss-[2-bromo-3(S)-hydroxy-4(S)-fluoro-5- cyclohexyl-pent-trans-1-enyl]-1a-cyclopentane acetaldehyde-y-lactol-bis-THP- ether (1.7 g) in dry DMSO (15 ml) was added to the obtained mixture.
The reaction was completed in about 1 hour, then the mixture was quenched with water and extracted with diethyl ether. The solvent was removed and the crude product purified with preparative chromatography on silica gel using ethylacetate/hexane = 1/1 as eluent: 1.650 g of 5c-9a,l 1 a,1 5(R)-trihydroxy-1 6(5)- fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic-acid N,N-dimethyl-amide 11,1 5-bis-THP-ether as pure product were obtained: [a]D = + 42,5 (C=l EtOH).Following the same procedure and using the appropriate triphenylphosphonium derivatives and the suitable bis-THP-ether-lactols, the amides, the
N,N-dimethy--amides, the pyrazolidin-amides, the piperidin-amides and the morpholin-amides as 11,1 5-bis- THP-ethers crude products, useful for the subsequent reactions and optionally purified by chromatographic tecnique, of the following acids were obtained:: 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(S)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid;; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 8,1 9,20-trinor-l 7-cyclopentyl-prost-5-en-1 3-ynoic acid; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tretranor-16-cyclohexyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-enj-13-ynoic acid; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-l 6(S)4luoro-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(S)-fluoro-I 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid; ; 5c-9a,1 1 a,l 5(R,S)-trihydroxy-l 6(S)4luoro-1 6-methyl-18,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(R)4luoro-l 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid, and 5-9α,11α,15(R)-trihydroxy-16(R)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid.
Example 3
1.5 ml of Jones reagent were dropped into a solution, cooled to -225"C, of 5c-9a,1 la,l 5(R)-trihydroxy- 16-(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide 11,15-bis-THP-ether (1.07 g) in acetone (15 ml). After the addition the temperature was allowed to rise to -8 C and the reacting mixture was
stirred for 20 minutes. The mixture was then diluted with benzene, washed with saturated (NH4)2SO4
aqueous solution until neutral, dried and the solvent was evaporated at 200C under vacuum. The residue
(0.830 g) was dissolved in 30 ml of acetone and treated with 1 N oxalic acid solution (5.5 ml) for 8 hours at
40 C.
After the reaction was completed the acetone was evaporated under vacuum to give a residue, which through chromatography an SiO2 using ethylacetate/cyclohexane = 36/65 as eluent affords 0.325 g of pure 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide : [a]D = - 33,0; [a]355=- 199.2 (C=1 EtOH).
By proceeding analogously the following compounds were obtained: 5c-9-oxo-11α,15(S)-dihydroxyu-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D= - 6,2; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid amide [a]D= - 7,6; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D= - 9,8; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D= - 10,2; 5c-9-oxo-11α;,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D= - 6,9; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide [α]D=-7,7; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide[a]D= - 7,2; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D= - 16,8; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D=-11,6; 5c-9-oxo-11α;,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide [α]D=-9,1; 5c-9-oxo-11α,15(R)-dihydroxy-16(R)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide [a]0 - 13,5; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D=-10,2; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide[a]D= - 38,2; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide [a]D= - 20,2; 5c-9-oxo-11α;,15(S)-dihydroxy-17,18,19,20-0tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide [α]D= - 12,8; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide [a]D= - 13,1; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide [a]D= - 42,4; 5c-9-oxo-l 1 a,1 5(R,S)-dihydroxy-1 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide [a]D= - 37,7; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-l 6-methyl-1 8,1 9,204rinor-17-cyclohexyl-prost-5-en-1 3-ynoic acid amide [a]D= - 56,6;; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide[a]D= - 37,8; 5c-9-oxo-l 1 a,1 5(R,S)-di hydroxy-1 6(R)4luoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid amide [α]D=-35,1; 5c-9-oxo-11α,15(R)-dihydroxy-16(R)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-1 1 a,l 5(S)-dihvdroxv-20-nor-1 9-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α;,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl
amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide;
5c-9-oxo-1 1 α, 15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R~-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; Sc-9-oxo-1 1 a,1 5(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; ; 5c-9-oxo-11 a,1 5(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11 a,1 5(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide;
5c-9-oxo-11 a,1 5(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-1 1 a,l 5(R,S)-dihydroxy-1 6(S)4luoro-1 8-1 9-20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-l 1 a,l 5(R)-dihydroxy-1 6(S)4luoro-1 8,1 9,20-trinor-1 7-cyclopentyl-prost-5-en-1 3-ynoic acid N,Ndimethyl-amide; 5c-9-oXo-11a,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide;; 5c-9-oxo-l 1 a,1 5(S)-dihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide; 5c-9-oxo-1 1 a,l 5(S)-dihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclopentyl-prost-5-en-1 3-ynoic acid N,Ndimethyl- amide; Sc-9-oxo-1 1 a,1 5(R)-dihydroxy-l 6(S)4luoro-l 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-1 3-ynoic acid
N,N-dimethyi-amide; 5c-9-oxo-l 1 a,1 5(R,S)-dihydroxy-l 6(S)-fluoro-1 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-1 3-ynoic acid
N,N-dimethylamide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α;,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(R)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9-oxo-11α;,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide;
5c-9-oxo-1 1 α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-1 1 α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α;,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide;
5c-9-oxo-1 1 α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(S)-=dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide;
5c-9-oxo-1 1 α;,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9-oxo-l 1 a,l 5(R)-dihydroxy-l 6(S)4luoro-1 7,18,1 9,20-tetrnnor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid pyrazoldin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9-oxo-l 1 a,l 5(R,S)-dihydroxy-l 6(S)4luoro-l 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide;; 5c-9-oxo-l 1 a,l 5(R,S)-dihydroxy-1 6(R)4luoro-l 6-methyl-1 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-I 3-ynoic acid pyrazolidin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(R)-fluoro-18,19,20-trinor-167-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-1 1 a,1 5(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-1 1 a,1 5(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide;
5c-9-oxo-11 α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid piperidin amide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(S)4luoro-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid piperidinamide;;
5c-9-oxo-1 1 a,1 5(S)-dihydroxy-1 9,20-dinor-l 8-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide;
5c-9-oxo-1 1 a,1 5(S)-dihydroxy-1 9,20-dinor-1 8-cyclopentyl-prnst-5-en-1 3-ynoic acid piperidin-amide; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-1 9,20-dinor-l 8-cyclohexylprnst-5-en-1 3-ynoic acid piperidinamide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(R)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid piperidinamide; 5c-9-oxo-l 1 a,1 5(S)-dihydroxy-l 8,1 9,204rinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide; 5c-9-oxo-11 a,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide;; 5c-9-oxo-11 a,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cycloheXyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-l 1 a,l 5(R,S)-dihydroxy-1 6(S)4luoro-1 8-1 9-20-trinor-1 7-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-1 8,1 9,204rinor-1 7-cyclopentyl-prost-5-en-1 3-ynoic acid piperidin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid piperidinamide; 5c-9-oxo-1 1 α;,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid piperidinamide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(S)-fluoro-l 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide; amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9-oxo-l 1 a,1 5(R,S)-dihydroxy-l 6(R)4luoro-l 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid piperidin-amide;
5c-9-oxo-1 1 α,15(R)-dihydroxy-16(R)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin- acid morpholin-amide;
5c-9-oxo-1 1 a,1 5(S)-dihydroxy-20-nor-l 9-cyclohexyl-prost-5-en-l 3-ynoic acid morpholin-amide;
5c-9-oxo-11 a,1 5(S)-dihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9-oxo-11α;,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclo-hexyl-prost-5-en-13-ynoic acid morpholinamide;
5c-9-oxo-1 1 α-15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-1 1 α;,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid mor
pholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α ;,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid morpholin
amide; 5c-9-oxo-1 1 a,1 5(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid morpholin
amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid
morpholin-amide; 5c-9-oxo-11 a,1 S(R,S)-dihydroxy-l 6(S)-fluoro-17,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-l 3-ynoic acid
morpholin-amide; 5c-9-oxo-1 1 a,l 5(R)-dihydroxy-1 6(S)-fluoro-l 6-methyl-i 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-l 3-ynoic acid morpholin-amide;; 5c-9-oxo-11 a,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cycloheXyl-prost-5-en-13-ynoic acid morpholin-amide; and 5c-9-oxo-l 1 a,l 5(R,S)-dihydroxy-1 6(R)-fluoro-1 6-methyl-l 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide.
Example 4
Potassium tert. butoxide (3.2 g) was dissolved in 20 ml of dry DMSO under dry nitrogen and triphenylphosphonium pentanoic acid amide bromide (6.3 g) was added to the solution under stirring with magnetic stirrer.
The temperature was kept below 30"C through water bath and a solution of 3a,5a-dihydrnxy-2i3-[2-brnmo- 3(S,R)-hydroxy-4(S)-fluoro-4-methyl-5-cyclopentyl-pent-trans-1 -enyl 1-1 a-cyclopentane aceta Idehyde-y- lactol-l5-trimethylsilyl ether (1.9 g) in DMSO (8 ml) was added to the previously obtained mixture. After the reaction was completed the mixture was diluted with cold water and then extracted with diethyl ether.The solvent was removed and the crude product, obtained as 15-deprotected during the Wittig reaction, was purified through chromatography thus giving 1.8 g of 5c-9a,-1 la,I 5(S,R)-trihydroxy-l 6(S)4luoro-l 6-methyl- 18,19,20-trinor-l7-cyclopentyl-prost-5-en-13-ynoicacid amide: [a]D= + 14,95; [a]35=5+ 54,2 (C=l EtOH).
By proceeding analogously the following compounds were obtained: 5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid amide: 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c,9a,l 1 a, 1 5(S)4rihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid am ide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)-fiuorn-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide;; 5c-9a,1 1 a,l 5(R)-trihydroxy-l 6(S)4luoro-l 6-methyl-i 8,1 9,204rinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9a,1 1 a,1 5(R,S)-tnhydrnxy-1 6(S)-fluoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,l 1 a,1 5(R)-trihydroxy-1 6(R)Jluoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid N,N-dimethyl-amide; 5c-9a,l 1 ol,l 5(S)-trihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 3-ynoic acid N,N-dimethyl-amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide;
5c-9a,1 1 α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(S)-fluoro-1 9,20-dinor-l 8-cyclohexyl-prost-5-en-I 3-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α ;,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9a,11 α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9a,11 a,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide;; 5c-9a,I 1 a,1 5(S)4rihydroxy-l 7,18,1 9,204etranor-l 6-cyclohexyl-prnst-5-en-1 3-ynoic acid N,N-dimethylamide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-l 6-cyclopentyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α;,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9a,1 1 a,1 5(R)4ri hydroxy-l 6(R)4luoro-l 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid
N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide;
5c-9a,1 1 a,1 5(S)-trihydroxy-20-nor-l 9-cyclopentyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide;
5c-9a,1 1 α-15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9α,11α;,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9α,11α,15(R,S)trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9a,1 1 α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide;
5c-9a,l 1 α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-1 6(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid pyrazolidinamide; 5c-9α;,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclhexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,l 1 a, 1 5(R,S)-tri hyd roxy-1 6(S)4luoro-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,l 5(R)-trihydroxy-1 6(R)-fluoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid pyrazolidin-amide;; 5c-9a,l 1 a, 1 5(S)4rihydroxy-20-nor-l 9-cyclohexyl-prost-5-en-I 3-ynoic acid pyrazolidin-amide; 5c-9a,1 1 a,l 5(S)-trihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-1 ic acid pyrazolidin-amide; 5c-9a,l 1 α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid pyrazolidin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid piperidinamide; 5c-9a,I 1 α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid piperidin; 5c-9a,11 α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperidinamide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-l 8,1 9,204rinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide;; 5c-9a,1 1 a,1 5(R)4rihydroxy-l 6(S)-fluoro-l 8,1 9,20-trinor-1 7-cyclopentyl-prost-5-en-1 3-ynoic acid piperidinamide; 5c-9a,11 a,15(R,S)-trihydroxy-16(S)-fluoro-18,19,1 û-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9a,1 I a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide; 5c-9a,11a,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyciopentyl-prost-5-en-13-ynoicacid piperidin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid piperidin-amide; 5c-9a,1 1 a,l 5(R,S)-trihydroxy-1 6(S)-fluoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid
piperidin-amide;; 5c-9a,l 1 a,1 5(R)-trihydroxy-l 6(S)4luoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid
piperidin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)-fluoro-l 6-methyl-1 8,1 9,20-trinor-l 7-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(R)-fluoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid piperidin-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-0prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide;; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9a,l 1 a,1 5(S)-trihydroxy-1 9,20dinor-1 8-cyclopentyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α;,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c,9a,1 1 a,1 5(S)4rihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9α,11α;,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9a,11 α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9a,1 I a,l 5(R,S)-trihydroxy-1 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-l 6(S)-fluoro-1 6-methyl-1 8,1 9,204rinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide;; 5c-9a,1 1 a,1 5(R)-trihydroxy-l 6(R)-fluoro-1 6-methyl-1 8,1 9,20-tnnor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; and 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperazinamide.
Example 5 Asolution of 5c-9-oxo-11α15(S)-dihydroxy-16(R)-fluoro-18,19,20-trinor-17-cycloheptyl-prost-5-en-13-ynoic acid piperidin-amide 1 1,15-bis-THP-ether (0.57 g) in acetone (10 ml), treated with 1 N aqueous oxalic acid (lOmI) was refluxed for 7 hours. The acetone in excess was removed under vacuum and the solution was extracted with diethyl ether. The organic extract was concentrated and absorbed on acid-washed silica-gel.
Elution with benzene/diethyl ether afforded 0.21 g of 5c-9-oxo-l 5(S)-hydroxy-1 6(R)4luoro-1 8,1 9,20-trinor-1 7- cycloheptyl-prosta-5,10-dien-13-ynoic acid piperidin-amide: [a]D= + 2.5 (C=1 EtOH). By using the same procedure, starting from 9-oxo-1 1,1 5-bis-THP-ether intermediate derivatives obtained according to Example 3, the following compounds were prepared:: 5c-9-oxo-1 5(S)-hydroxy-20-nor-l 9-cyclohexyl-prosta-5, 1 0-dien-l 3-ynoic acid amide; 5c-9-oxo-I 5(S)-hydroxy-20-nor-1 9-cyclopentyl-prosta-5,l 0-dien-1 3-ynoic acid amide; 5c-9-oxo-l 5(R)-hydroxy-1 6(S)4luoro-20-nor-1 9-cyclohexyl-prosta-5,1 0-dien-l 3-ynoic acid amide; 5c-9-oxo-1 5(R,S)-hydroxy-1 6(S)-fl uoro-20-nor-l 9-cyclohexyl-prosta-5,1 0-dien-l 3-ynoic acid am ide; 5c-9-oxo-15(S)-hydroxy-19,20-dinor-18-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(S)-hydroxy-19,20-dinor-18-cyclopentyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(R)-hydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(R,S)-hydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;;
5c-9-oxo-15(S)-hydroxy-18,19,20-trinor-17-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(S)-hydroxy-18,19,20-trinor-17-cyclopentyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(R)-hydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexylprosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(S,R)-hydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(R)-hydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(R,S)-hydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(S)-hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,10-dien-13-ynoic acid amide;
5c-9-oxo-15(S)-hydroxy-17,18,19,20-tetranor-16-cyclopentyl-prosta-5,10-dien-13-ynoic acid amide;; 5c-9-oxo-l 5(R)-hydroxy-l 6(S)-fluoro-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prosta-5,1 0-dien-l 3-ynoic acid amide; 5c-9-oxo-1 S(R,S)-hydroxy-l G(S)-fluoro-17,18,1 9,20-tetranor-l 6-cyclohexyl-prosta-5,1 O-dien-13-ynoic acid amide; 5c-9-oxo-1 S(R)-hydroxy-l G(S)-fluoro-l 6-methyl-18,1 9,20-trinor-l 7-cyclohexyl-prosta-5,1 O-dien-l 3-ynoic acid amide; 5c-9-oxo-l 5(R,S)-hydroxy-1 6(S)4luoro-1 6-methyl-l 8,1 9,20-trinor-l 7-cyclohexyl-prosta-5,1 0-dien-1 3-ynoic acid amide; and 5c-9-oxo-1 5(R,S)-dihydroxy-1 6(R)4luoro-1 6-methyl-I 8,1 9,20-trinor-l 7-cyclohexyl-prosta-5,1 0-dien-1 3- ynoic acid amide.
Example 6 To a solution of 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid piperazin-amide (0.2 g) in 95% ethyl alcohol (5 ml) a stoichiometric amount of 1 N HCI was added. The solvent was evaporated to dryness thus giving 5c-9a,1 1 α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17- cyclohexyl-prost-5-en-1 3-ynoic acid piperazin-amide hydrochloride as white crystals.
Example 7 5c-9a,1 la,l 5(R)-Trihydroxy-1 6(S)4luoro-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid-N,N- dimethylamide 11,1 5-bis-THP-ether (0.65 g) was dissolved in 10 ml of dry CC14 and 0.5 ml of pyridine, then 0.1 ml of acetylchloride were dropped into the solution.
The solution was stirred for about 2 hrs at room temperature and neutralized with 10% NaH2PO4 solution and extracted with diethylether.
The solvent was removed and the crude product was purified chromatographically on silica gel using ethylacetate/cyclohexane=80/20 as diluent.
The pure 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid- N,N-dimethylamide 11,1 5-bis-THP-ether-9-acetate was collected and dissolved in a mixture of acetone (10 ml) and 1 N oxalic acid (10 ml) and stirred for 6 hrs at 400C. The reaction solution was diluted with 10 ml of
H2O, the acetone was distilled and the mixture extracted with ethylether.
The crude product was purified on silica gel using ethyl acetate/cyclohexane= 50/50 as eluent, thus giving 0.320 mg of pure 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide-9-acetate [alD= + 76,2 (c= 1 EtOH).
By proceeding analogously the 9-acetate derivatives of all the compounds reported in Example 1 were obtained.
FORMULATION EXAMPLES
Formulation I
Tablet (1 mg)
Tablets, each weighing 80 mg and containing 1 mg of the active substance, are manufactured as follows:
Composition (for 100.000 tablets) 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19 20-trinor-l 7-cyclohexyl-prost-5-en-l 5-ynoic acid amide 100 g
Lactose 5000 g
Corn starch 2720 g
Talc powder 150 g
Magnesium stearate 30 g 5c-9a,1 1 a,1 5(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-1 7-cyclohexyl-prost-5-en-l acid acid amide, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size.
Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder.
The granules are dried, comminuted on a sieve of mesh size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 5 mm diameter.
Formulation II
Capsule (1 mg) 5c-9a,11 a,15(R)-trihydroxy-16(S)-fluoro-18,19, 20-trinor-l 7-cyclohexyl-prost-5-en-l 3-ynoic acid amide 1.0 mg
Lactose 89.8 mg
Corn starch 9.0 mg
Magnesium stearate 0.2 mg
Total 100.0 mg
This formulation was encapsulated in two-piece hard gelatin capsules.
Claims (9)
1. Optically active or racemic prostaglandin derivatives of formula (I)
wherein
each of R' and R" represents, independently, hydrogen, C1-C6 alkyl, aryl or heterocyclyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring;
the symbol ---- represents a single or a double bond, wherein::
a) when the symbol -- is a double bond, R1 is a hydrogen atom and R2 and R3, taken together, form an oxo group;
b) when the symbol = is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or acyloxy or R2 and
R3, taken together, form an oxo group;
one of R4 and R5 is hydroxy and the other is hydrogen;
each of R5 and R7 represents, independently, hydrogen, C1-C4 alkyl or fluorine;
niszero,1,2 or 3;
R8 represents a C3-C7 cycloalkyl ring unsubstituted or substituted by one or more substituents chosen from a') halogen; b') trihalo-C-C6-alkyl; c') C1-C4 alkyl; d') C1-C4 alkoxy; e') phenyl; and f') phenoxy; and the pharmaceutically or veterinarily acceptable salts thereof.
2. A compound according to claim 1, wherein R' and R" are, independently, hydrogen or C1-C4 alkyl; or R' and R", taken together with the nitrogen atom to which they are linked, form a pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl or morpholino ring;
the symbol = is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or acyloxy or R2 and R3, taken together, form an oxo group; Re represents a radical chosen from cyclopentyl, cyclohexyl and cycloheptyl, each of them being unsubstituted or substituted by one or more a') halogen, b') trihalo-C1-Ce-alkyl, c') C1-C4 alkyl, d') C1 -C4 alkoxy, e') phenyl, f') phenoxy;R4, R5, Re, R7 and n are as defined in claim 1 and the pharmaceutically or veterinarily acceptable salts thereof.
3. A compound according to claim 1, wherein R' and R" are, independently, hydrogen or methyl; or R' and R", taken together with the nitrogen atom to which they are linked, form a piperidino or morpholino ring;
the symbol = is a single bond, R1 is hydroxy, R2 is hydrogen and R3 is hydroxy or R2 and R3, taken together, form an oxo group;
each of R6 and R7 represents, independently, hydrogen, methyl or fluorine;
R4, Rg and n are as defined in claim 1; Re is cyclopentyl or cyclohexyl; and the pharmaceutically or veterinarily acceptable salts thereof.
4. A compound selected from the group consisting of: 5c-9a,l I a,l 5(S)-trihydroxy-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)4rihydroxy-20-nor-l 9-cyclopentyl-prost-5-en-1 3-ynoic acid amide: 5c-9a,l 1 a,1 5(R)-trihydroxy-l 6(S)4luoro-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,I 5(R,S)-trihydroxy-I 6(S)-fluoro-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9a,11 a,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide;; 5c-9a,1 1 a,1 5(R)-trihyd roxy-1 6(S)4l uoro-l 9,20-dinor-l 8-cyclohexyl-prost-5-en-1 3-ynoic acid amide;
5c-9a,1 1 a,I 5(R,S)-trihydroxy-1 6(R)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 8,1 9,20-trinor-I 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9a,1 1 a,1 5(S)-trihydroxy-1 8,19,20-trinor-1 7-cyclopentyl-prnst-5-en-1 3-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9a,l la,l 5(S)-trihydroxy-17,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9α,11α,15(S)-trihydroxy17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9α,11α;,15(R)-trihydroxy-16(S)-fluoro-16-methyl-18,19,20-trior-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9a,1 1 a,1 5(R,S)-trihydroxy-1 6(S)4luoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9a,1 1 a,1 5(R)-trihydroxy-1 6(R)4luoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide;
5c-9a,l 1 a,l 5(S)-trihydroxy-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α;,15(R,S)-trihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(S)-trihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R,S)-trihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(S)-trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α;,15(S)-trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl amide; 5c-9a,l 1 a,l 5(R,S)4rihydroxy-l 6(S)4luoro-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid N,Ndimethyl-amide; 5c-9a,1 1 α,15(R)-trihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9α,11α,15(R,S)-trihydroxy-16(S)-fluoro-18,19,10-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9a,l 1 a,1 5(S)-trihydroxy-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethylamide; ; 5c-9α,11α,15(S)-trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9α,11α,15(R)-trihydroxy-16(S)-fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9a,l 1 a,1 5(R,S)-trihydroxy-l 6(S)4luoro-1 7,18,1 9,20-tetranor-I 6-cyclohexyl-prost-5-en-1 3.ynoic acid
N,N-dimethyl-amide; 5c-9a,1 1 a,l 5(R)-trihydroxy-1 6(S)Jluoro-1 6-methyl-1 8,1 9,20-trinor-1 7-cyclohexyl-prnst-5-en-1 3-ynoic acid
N,N-dimethyl-amide; 5c-9a,1 1 a,l 5(R,S)-trihydroxy-l 6(S)4l uoro-1 6-methyl-l 8,1 9,20-trinor-1 7-cyclohexyl-prost-5-en-1 3-ynoic acid N,N-dimethyl-amide;; 5c-9a,l 1 a,1 5(R)-trihydroxy-1 6(R)4luoro-1 6-methyl-1 8,1 9,20-trinor-17-cyclohexyl-prost-5-en-l 3-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-1 1 a,1 5(S)-dihydroxy-20-nor-1 9-cyclohexyl-prost.5-en-1 3-ynoic acid amide; 5c-9-oxo-l 1 a,1 5(S)-dihydroxy-20-nor-1 9-cyclopentyl-prost-5-en-l 3-ynoic acid amide; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-l 6(S)4luoro-20.nor-1 9-cyclohexyl-prost-5-en-l 3-ynoic acid amide; 5c-9-oxo-l 1 a,1 5(R,S)-dihydroxy-1 6(S)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α;,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide;; 5c-9-oxo-1 1 a,l 5(R,S)-dihydroxy-l 6(S)4luoro-1 8-1 9-20-trinor-7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-l 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-l 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide;; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(S)-fluoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid amide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(R)4luoro-1 6-methyl-1 8,1 9,20-trinor-I 7-cyclohexyl-prost-5-en-1 3-ynoic acid amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide;; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-20-nor-l 9-cyclohexyl-prost-5-en-1 3-ynoic acid N,N-dimethylamide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-l 6(S)4luoro-20-nor-1 9-cyclohexyl-prost-5-en-1 3-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide;; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide;
5c-9-oxo-11 α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid N,Ndimethyl-amide;; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-ynoic acid N,N-dimethylamide; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)4luoro-17,1 8,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-1 3-ynoic acid
N,N-dimethyl-amide; 5c-9-oxo-1 1 a,l 5(R,S)-dihydroxy-l 6(S)4luoro-1 7,18,1 9,204etranor-1 6-cyclohexyl-prost-5-en-l 3-ynoic acid
N,N-dimethyl-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α;,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(R)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid N,N-dimethyl-amide; 5c-9-oxo-1 1 a,I 5(S)-dihydroxy-20-nor-1 9-cyclohexyl-prnst-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide;
5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-1 1 α,15(R,S)-dihydroxy-16(S)-fluoro-20-nor-19-cyclohexyl-prost-5-en-13-ynoic acid morpholin.
amide; 5c-9-oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-1 1 α, 15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide;
5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide; 5c-9-oxo-1 1 a,l 5(R,S)-dihydroxy-l 6(R)4luoro-20-nor-l 9-cyclohexyl-prnst-5-en-l 3-ynoic acid morpholinamide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide;; 5c-9-oxo-1 1 α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-18-19-20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-1 1 α,15(R,S)-dihydroxy-16(S)-fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-lla,l S(S)-dihydroxy-17,1 8,19,20-tetranor-1 6-cyclohexyl-prost-5-en-13-ynoic acid morpholinamide;; Sc-9-oxo-1 1 a,I 5(S)-dihydroxy-l 7,18,1 9,20-tetranor-l 6-cyclopentyl-prost-5-en-1 3-ynoic acid morpholinamide; 5c-9-oxo-1 1 a,1 5(R)-dihydroxy-1 6(S)-fluoro-1 7,18,1 9,20-tetranor-1 6-cyclohexyl-prost-5-en-I 3-ynoic acid morpholin-amide; 5c-9-oxo-1 1 a,1 5(R,S)-dihydroxy-1 6(S)-fluoro-1 7,18,1 9,20-tetranor-l 6-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide; 5c-9-oxo-11α,15(R,S)-dihydroxy-16(S)-fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynoic acid morpholin-amide;
and 5c-9-oxo-l 1 a,1 5(R,S)-dihydroxy-1 6(R)4luoro-l 6-methyl-l 8,1 9,20-trinor-17-cyclohexyl-prost-5-en-1 3-ynoic acid morpholin-amide.
5. Process for the preparation of compounds of formula (I) according to claim 1, the process comprising:
a) reacting a reactive derivative of an optically active or racemic compound of formula (II)
wherein
when the symbol = represents a double bond, R'1 is a hydrogen atom and R2 and R'3, taken together, form an oxo group while, when the symbol = represents a single bond, R'1 is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom, R2 is hydrogen, R'3 is hydroxy, acyloxy or a protecting group bound to the ring through an ethereal oxygen atom or R2 and R'3, taken together, form an oxo group; one of R'4 and R'5 is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and Re, R7, n and Re are as defined in claim 1, with a compound of formula (111)
wherein
R' and R" are as defined in claim 1, thus giving an optically active or racemic compound of formula (IV)
wherein
R",R'3,R2,R'1,R'4,R'5,R6,R7, n and R8 are as defined above and then, when necessary, removing the hydroxy protecting groups; or
b) reacting an optically active or racemic compound of formula (V)
wherein
M represents -C=C- or
and Xis bromine, chlorine or iodine;Z is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom; one of R'4 and R'5 is hydroxy or a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and Re, R7, n and Re are as defined in claim 1, with a Wittig reagent containing a group
wherein R' and R" are as defined in claim 1, to give an optically active or racemic compound of formula (Vl)
wherein
R', R , Z, R'4, R's, Re, R7, n and Re are as defined above which, when the 11- and 15-hydroxy groups are in the protected form, if desired, may be esterified to give a 9a-acyloxy derivative of a compound of formula (VI) and then removing the protecting groups at the 11 - and/or 15-positions, if present, both in a compound of formula (VI) and in its acyloxy derivatives, thus giving a compound of formula (I), wherein R3 is hydroxy or acyloxy, R2 is hydrogen, R1 is hydroxy, the symbol = represents a single bond and R', R", R4, Rsx R6, R7, n and R8 are as defined in claim 1; or
c) oxidizing an optically active or racemic compound of formula (VII)
wherein
Z' is a protecting group bound to the ring through an ethereal oxygen atom; one of R"4 and R"5 is a protecting group bound to the ring through an ethereal oxygen atom and the other is hydrogen; and R', R", Re, R7, n and R8 are as defined in claim 1, to give an optically active or racemic compound of formula (VIII)
wherein
R', R , Z', R , R"5, R6, R7, n and Re are as defined above, which, in turn, is subjected to the removal of the ether protecting groups to give, depending on the reaction conditions, either a compound of formu la (I), where ---- is a single bond, R1 is hydroxy, R2 and R3, taken together, form an oxo group and R', R", R4, Re, Re, R7, n and R8 are as defined in claim 1 or a compound of formula (I), where = is a double bond, R1 is hydrogen, R2 and R3, taken together, form an oxo group and R', R", R4, R5, R6, R7, n and Re are as defined in claim 1; and/or, if desired, salifying a compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof, and/or, if desired, resolving a mixture of isomers into the single isomers.
6. An optically active or racemic compound of formula (IV)
wherein
R', R", R'3, R2, R'1, R'4, R'5, Re, R7, n and R8 are as defined in claim 5 and the pharmaceutically or veterinarily acceptable salts thereof.
7. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to any one of claims 1 to 4 and 6, or a pharmaceutically acceptable salt thereof.
8. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4 and 6, for use in a method of treatment of the human or animal body by surgery a therapy or a diagnosis practised on the human or animal body.
9. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4 and 6, or a pharmaceutical composition according to claim 7 for use in administration to human patients or animal to induce labor or to expel a dead fetus in pregnant females, to control fertility in females, to reduce or eliminate the formation of gastrointestinal ulcers, to accelerate the healing process of ulcers present in the gastrointestinal tract and for reducing the undesirable gastrointestinal side-effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08231938A GB2130575B (en) | 1982-11-09 | 1982-11-09 | Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins |
| DE19833338327 DE3338327A1 (en) | 1982-11-09 | 1983-10-21 | AMIDE DERIVATIVES OF 13,14-DIDEHYDRO-CYCLOALKYL-PROSTA-GLANDINES |
| BE0/211834A BE898169A (en) | 1982-11-09 | 1983-11-07 | Amide derivatives of 13,14-didehydro-cycloalkyl-prostaglandins. |
| JP58207657A JPS59101459A (en) | 1982-11-09 | 1983-11-07 | Prostaglandin derivative, manufacture and pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08231938A GB2130575B (en) | 1982-11-09 | 1982-11-09 | Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2130575A true GB2130575A (en) | 1984-06-06 |
| GB2130575B GB2130575B (en) | 1985-12-11 |
Family
ID=10534131
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08231938A Expired GB2130575B (en) | 1982-11-09 | 1982-11-09 | Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS59101459A (en) |
| BE (1) | BE898169A (en) |
| DE (1) | DE3338327A1 (en) |
| GB (1) | GB2130575B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2009145A (en) * | 1977-11-15 | 1979-06-13 | Erba Carlo Spa | Didehydro-prostaglandins |
| GB2111986A (en) * | 1981-11-27 | 1983-07-13 | Erba Farmitalia | Ester and amide derivatives of 13 14-didehydro prostaglandins |
-
1982
- 1982-11-09 GB GB08231938A patent/GB2130575B/en not_active Expired
-
1983
- 1983-10-21 DE DE19833338327 patent/DE3338327A1/en not_active Withdrawn
- 1983-11-07 BE BE0/211834A patent/BE898169A/en not_active IP Right Cessation
- 1983-11-07 JP JP58207657A patent/JPS59101459A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2009145A (en) * | 1977-11-15 | 1979-06-13 | Erba Carlo Spa | Didehydro-prostaglandins |
| GB2085872A (en) * | 1977-11-15 | 1982-05-06 | Erba Farmitalia | 13,14-didehydro-prostaglandins |
| GB2086373A (en) * | 1977-11-15 | 1982-05-12 | Erba Farmitalia | 13,14-didehydro-prostaglandins |
| GB2111986A (en) * | 1981-11-27 | 1983-07-13 | Erba Farmitalia | Ester and amide derivatives of 13 14-didehydro prostaglandins |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2130575B (en) | 1985-12-11 |
| DE3338327A1 (en) | 1984-05-10 |
| BE898169A (en) | 1984-05-07 |
| JPS59101459A (en) | 1984-06-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |