GB1343014A - Prostaglandins and the preparation thereof - Google Patents

Prostaglandins and the preparation thereof

Info

Publication number
GB1343014A
GB1343014A GB588472A GB588472A GB1343014A GB 1343014 A GB1343014 A GB 1343014A GB 588472 A GB588472 A GB 588472A GB 588472 A GB588472 A GB 588472A GB 1343014 A GB1343014 A GB 1343014A
Authority
GB
United Kingdom
Prior art keywords
methyl
endo
hex
alkyl
oxobicyclo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB588472A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of GB1343014A publication Critical patent/GB1343014A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/27—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system containing six carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
    • 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
    • C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • 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
    • C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

1343014 Prostaglandins UPJOHN CO 8 Feb 1972 [5 March 1971] 5884/72 Heading C2C [Also in Divisions A5 and C3] The invention comprises novel prostaglandins of the formulµ wherein G is H, C 1-10 alkyl optionally substituted with 1, 2 or 3 fluorine atoms, C 2-10 alkyl substituted with 4 or 5 fluorine atoms on the omega and omega-minus-one carbon atoms, or a radical of the formula wherein C t H 2 t is a valence bond to C 1-10 alkylene optionally substituted by 1 or 2 fluorine atoms, with 1 to 7 carbon atoms between -CR 3 OH and the ring; T is C 1-4 alkyl, F 2 Cl, CF 3 or OR 9 , where R 9 is H, C 1-4 alkyl or 2- tetrahydropyranyl; s is 0 to 3, with the proviso that not more than 2 T's are other than alkyl and when 2 or 3 T's are present as substituents they may be the same or different; E is -CH 2 CHR 4 or trans-CH=CR 4 , where R 4 is H or C 1-4 alkyl when J is -CgHg-A-C p H 2p - O-C q H 2q , or E is trans-CH=CR 4 when J is cis or trans -C(R 5 )=C(R 6 )-M or -C#C-M, where C g H 2g is a valence bond or C 1-8 alkylene with 1 to 4 carbon atoms between -CHR 2 and A, C p H 2p is a valence bond or C 1-6 alkylene with 1 to 4 carbon atoms between A and O, C q H 2q is C 1-6 alkylene with 1 to 3 carbon atoms between O and COOR 1 , wherein C g H 2g , C p H 2p and C q H 2q together represent 1 to 20 carbon atoms with total chain lengths of 1 to 5 carbon atoms, A is a benzene ring; M is C j H 2j -A-C p H 2p -OC q H 2q , where C j H 2j is a valence bond or C 1-5 alky lene with 1 or 2 carbon atoms between = C(R 6 )- or # C- and A, with the proviso that the total carbon content of -C(R 6 )=C(R 6 )-C j H 2j - does not exceed 8, and C j H 2j , C p H 2p and C q H 2q together represent 1 to 17 carbon atoms with total chain lengths 1 to 3 carbon atoms; R 1 is H, C 1-8 alkyl, C 3-10 cycloalkyl, C 7-12 aralkyl, phenyl optionally substituted by 1 to 3 Cl or C 1-4 alkyl, or ethyl substituted in beta position by 3 chlorine atoms, 2 or 3 bromine atoms or 1, 2 or 3 iodine atoms; R 2 , R 3 , R 5 and R 6 each are H or C 1-4 alkyl, and # indicates attachment of a group to the cylopentane ring in alpha or beta configuration, the C 1-8 alkanoates thereof and pharmacologically acceptable salts thereof when R 1 is H, and their preparation. The PGE analogues-of the above formula in which R 1 is not H, and E is trans -CH=CR 4 - are prepared by reacting bicyclohexane derivatives of the formula when R 10 is the same as R 1 except that it is not H, G<SP>1</SP> is the same as G except that R 9 is not H, and R 13 is C 1-5 alkyl, obtained by treating the corresponding glycols with alkanesulphonyl halides, with water at 0‹ to 60‹ C. PGA esters of the above formula may be obtained by treatingthe above bicyclohexane derivative with combinations of water, bases characterized by their aqueous solutions having pH's of 8 to 12 and sufficient water-soluble organic diluents to form basic substantially homogeneous reaction mixtures at 40‹ to 100‹ C., or by dehydrating the corresponding PGE compound. Reduction of the PGE analogues obtained by the above method gives the corresponding PGF derivatives. PGB compounds are prepared by reacting the corresponding PGE or PGA derivatives with bases whose aqueous solutions have pH's greater than 10. The corresponding dihydro PGE, PGF, PGA, and PGA 1 compounds may be obtained by reducing the corresponding compounds containing double or triple carbon to carbon bonds. PGF compounds in which R 3 is C 3 is C 1-4 alkyl are preferably obtained by reacting compounds of the formula when R 8 is C 1-4 alkyl, C 7-12 aralkyl or optionally substituted phenyl, R 17 is R 1 as defined above or S 1 (R 8 ) 3 , and G<SP>11</SP> is the same as G above except in R 9 S 1 (R 8 ) 3 replaces H; with Grignard reagents of the formula R 3 MgHal, hydrolysing the resulting Grinard complexes and hydrolysing the silylated alcohols thus produced. The resulting PGF analogue may then be oxidized to the corresponding PGE derivatives. The resulting acids may be converted to esters and salts, esters hydrolysed and hydroxy groups acylated. The following intermediates are also prepared: dl - endo - 6 - (1 - heptenyl) - 3 - (1 - pyrrolidinyl)- bicyclo[3,1,0]hex-2-ene, methyl [m-(chloromethyl)phenoxy]acetate, (m-formylphenoxy) acetic acid and its methyl ester, methyl [m- (hydroxymethyl)phenoxy]acetate, 3-[(m-formyl)phenoxy]propionic acid and its methylester, methyl 3-[m-(hydroxymethyl)phenoxy] propionate, methyl 3-[m-(chloromethyl)phenoxy] propionate, ethyl [o-(bromomethyl)-benzyloxy]acetate, endo-6-(5-phenyl-cis-1-pentenyl)- bicyclo[3,1,0]hexan-3-one, endo-6(5-phenyl-cis- 1-pentenyl)-bioyclo[3,1,0]hexan-3-ol and its tetrahydropyran-2<SP>1</SP>-yl ether, endo-6(1,2-dihydroxy - 4 - phenylbutyl) - bicyclo[3,1,0]hexan- 3-one and its acetonide, [m-(3-bromo-1-propynyl)phenoxy]acetic acid and its methyl ester, m-(1,2-dibromoethyl)anisole, m-methoxyphenylacetylene, m-hydroxyphenylacetylene, m- (2-hydroxyethoxy)-phenylacetylene and its tetrahydropyran-2<SP>1</SP>-yl ether, 3-{m-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl} -propargyl alcohol and its ester, with methane sulphonic acid, 3-[m-(2-hydroxyethoxy)phenyl]propargyl bromide and its tetrahydropyran-2<SP>1</SP>-yl ether, methyl[o - (3 - bromo - 1 - propynyl)benzyloxy] acetate, methyl [m-(3-bromo-1-propynyl)benzyloxy]acetate, methyl [p-(3-bromo-1-propynyl) benzyloxy]acetate, methyl [m-(3-bromo-cis-1 propenyl)phenoxy]acetate and the corresponding trans isomer, 3-{m[2-(tetrahydropyran-2- yloxy)ethoxy]phenyl}prop-trans-2-enyl alcohol, methyl m-{3-[6-(4-phenyl-cis-1-butenyl)-3-oxobicyclo[3,1,0]hex - 2α - yl] - 1 - propynyl}- phenoxyacetate, methyl m-{3-(endoe-6-(1,2-dihydroxy - 4 - phenylbutyl) - 3 - oxobioyclo- [3,1,0]hex - 2α - yl) - 1 - propynyl}phenoxyacetate, ethyl m-{endo-[6-(1-heptenyl)-3-oxobicyclo[3,1,0] - hex - 2α - yl]methyl}benzyloxyacetate, ethyl m-{endo-[6-(1,2-dihydroxyheptyl)- 3 - oxobicyclo - [3,1,0]hex - 2α - yl]methyl}- benzyloxyacetate, methyl m-{[endo-6-(1-heptenyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl]methyl}- phenoxy acetate, methyl m{[endo-6-1,2-dihydroxyheptyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl]- methyl}phenoxyacetate, endo-6-(2-methyl-1- heptenyl) - 3 - oxobicyclo[3,1,0]hexan - 3 - one, endo - 6 - (1,2 - dihydroxy - 2 - methylheptyl)- bicyclo[3,1,0]-hexan-3-one and its acetonide, m - {3 - [endo - 6 - (1,2 - dihydroxy - 2 - methylheptyl) - 3 - oxobicyclo[3,1,0]hex- 2α - yl] - cis- 1 - propenyl]phenoxy - acetic acid acetonide and its methyl ester, methyl m-{3-[endo-6-(4-phenylcis - 1 - butenyl) - 3 - oxobicyclo[3,1,0]hex- 2α- yl]-1-propynyl}phenoxyacetate, methyl m- {3 - [endo - 6 - (1,2 - dihydroxy - 4 - phenylbutyl)- 3 - oxobicyclo[3,1,0]hex - 2α - yl] - 1 - propynyl}- phenoxyacetate, m-{3-[endo-6-(1,2-dihydroxy- 2 - methylheptyl) - 3 - hydroxybicyclo[3,1,0]- hex - 2α - yl] - 1 - propenyl}phenoxyacetic acid and its methyl and 2,2,2-trichloroethyl esters, o - {[endo - 6 - (1 - heptenyl) - 3 - oxobicyclo- [3,1,0]hex-2α-yl]methyl}-phenoxy acetic acid, o - {[endo - 6 - (1 - heptenyl) - 3 - hydroxybicyclo[3,1,0]hex - 2α - yl]methyl}phenoxyacetic acid and its methyl ester, and dl-15-dehydro-3- oxa-3,7 - inter - m - phenylene-4,5,6 - trinor- PGF 1 a methyl ester.
GB588472A 1971-03-05 1972-02-08 Prostaglandins and the preparation thereof Expired GB1343014A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12157271A 1971-03-05 1971-03-05

Publications (1)

Publication Number Publication Date
GB1343014A true GB1343014A (en) 1974-01-10

Family

ID=22397574

Family Applications (1)

Application Number Title Priority Date Filing Date
GB588472A Expired GB1343014A (en) 1971-03-05 1972-02-08 Prostaglandins and the preparation thereof

Country Status (8)

Country Link
AU (1) AU456177B2 (en)
BE (1) BE780216A (en)
CH (3) CH580581A5 (en)
DE (1) DE2209990A1 (en)
FR (1) FR2128629B1 (en)
GB (1) GB1343014A (en)
NL (1) NL7202825A (en)
ZA (1) ZA72645B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042268A2 (en) * 2000-11-27 2002-05-30 Pfizer Products Inc. Ep4 receptor selective agonists in the treatment of osteoporosis

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042268A2 (en) * 2000-11-27 2002-05-30 Pfizer Products Inc. Ep4 receptor selective agonists in the treatment of osteoporosis
WO2002042268A3 (en) * 2000-11-27 2002-07-25 Pfizer Prod Inc Ep4 receptor selective agonists in the treatment of osteoporosis
US6552067B2 (en) 2000-11-27 2003-04-22 Pfizer Inc. EP4 receptor selective agonists in the treatment of osteoporosis
US6747054B2 (en) 2000-11-27 2004-06-08 Pfizer Inc. EP4 receptor selective agonists in the treatment of osteoporosis
US7192979B2 (en) 2000-11-27 2007-03-20 Pfizer Inc. EP4 receptor selective agonist in the treatment of osteoporosis

Also Published As

Publication number Publication date
FR2128629A1 (en) 1972-10-20
BE780216A (en) 1972-09-04
CH580072A5 (en) 1976-09-30
AU456177B2 (en) 1974-12-12
CH580580A5 (en) 1976-10-15
AU3892172A (en) 1973-08-16
FR2128629B1 (en) 1975-08-01
CH580581A5 (en) 1976-10-15
DE2209990A1 (en) 1972-09-21
ZA72645B (en) 1972-11-29
NL7202825A (en) 1972-09-07

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PCNP Patent ceased through non-payment of renewal fee