CA2143117A1 - Tocolytic oxytocin receptor antagonists - Google Patents
Tocolytic oxytocin receptor antagonistsInfo
- Publication number
- CA2143117A1 CA2143117A1 CA002143117A CA2143117A CA2143117A1 CA 2143117 A1 CA2143117 A1 CA 2143117A1 CA 002143117 A CA002143117 A CA 002143117A CA 2143117 A CA2143117 A CA 2143117A CA 2143117 A1 CA2143117 A1 CA 2143117A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- mammal
- hydrogen
- compound
- mmol
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Compounds of the formula X-Y-Z-R1, wherein X is (I) or (II); W is hydrogen or acetate; Y is -CO-, -SO2- -CO(CH2)m-or -(CH2)m-; Z is N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m- or -CHCHOH-; R is hydrogen, C1-5 alkyl, C1-5 alkoxycar-bonylamino or quinuclidinylaminocarbonylamino; R1 is -CH3, -CH(CH3)2, C1-5 alkoxycarbonyl; aryl, heterocyclic and low-ercydoalkyl substituted by R2 and/or R3, -NR4R5 or -NCOR6; R2 is hydrogen, hydroxy, carboxyl, acetyl, nitro, halogen, mono-, di- or tri-C1-3 alkyl, spirocyclic indenyl, N-spiroindanepiperidinyl, O-R where R is as defined above, O-Het where Het is imidazole or benzimidazole or azimidobenzene, or where R2 is further defined as -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7, -(CH2)m-NR8R9, -(CH2)m-NHCO-(CH2)mR7, -(CH2)m-NHCO-CHR7R7, -(CH2)m-NHCO-CH=CHR7, -(CH2)m-CO-O-R7, -(CH2)m-CO-O-(CH2)mR7, -(CH2)m-CO-O-CHR7R7, -(CH)m-CO-O-CH = CHR7, -NHSO2R- where R is as defined above, NHSO2R7, -(CH2)m-O-R10, -SO2R10, -COR11, aryl loweralkyl, alkylsulfonylalkyl, alkylsulfonylalkylamido, R3 is one or two of hydrogen, hydroxyl or C1-5 alkyl; R4 is hydrogen, C1-5 alkyl, or C6 10 cycloal-kyl; R5 is hydrogen or acetyl; R6 is (A) or (B); R7 is alkylcarbamate alkyl, aryl alkyl or heterocyclyl alkyl substituted by R12, hydrogen, C1-4 alkyl, NSO2R12 or NHO-C1-4 alkyl; R8 is hydrogen or C1-5 alkyl; R9 is hydrogen or C1-5 alkyl; R10 is -CH3, alkaryl, alkarylalkyl or azimidobenzene; R11 is -CH3, aralkyl or heterocyclylalkyl; R12 is hydrogen, C1-5 alkyl or C1-5 al-koxy; and m is an integer of from 0 to 5. Such compounds are useful as oxytocin and vasopressin antagonists.
Description
~ WO94/0~496 214311 7 PCI/US93/09152 TITLE OF THE rNVENTION
TOCOLYTIC OXYTOCIN RECEPTOR ANTAGONISTS
FIELD OF THE ~VENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their m~mlf~cture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy. The aforementioned pharmacologic activities are useful in the treatment of m~mm~l~. More specifically, ~e compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Caesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
BACKGROUND OF THE INVENTION
In the field of obstetrics, one of the most i~nportant problems is the m~n~gement of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a le~clin~ cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents ~at are cullelllly in use include ~2-adrenergic agonists, m~gnesium sulfate and ethanol. Ritodrine, the le~(lin~ ~2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other ~2-adrenergic agonists, including ~ b~ line and albuterol have side effects simil~r to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular tr~n~mi~sion, respiratory depression and cardiac arrest, thus m~kinp this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature 21~3117 labor, but it does not produce a corresponding reduction in the inciden ce of fetal respiratory distress that ~tlmini~tration of ritodrine does.
It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has acc1lm~ ted 5 to strongly suggest that the hormone oxytocln may be a physiological initi~tor of labor in several m~mm~ n species including hllm~n~.
Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prost~ n-lin~ from the uterine endometriumldecidua. These prost~gl~n~lin~ may, in addition, be important in the cervical ripening process. By these mech~ni~m~, the process of labor (term and preterm) is initi~ted by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This "up-regulation" of oxytocin receptors and 5 enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prost~gl~nclin synthesis) effects of oxytocin on the uterus. A selective oxytocin blocker, or antagonist, would likely be more efficacious for treating preterm labor 20 than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few, if any, side effects.
The compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic 25 pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometriumL. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating 3 dysmenorrhea then current regimens. An additional use for the present invention is for the stoppage of labor preparatory to Caesarean delivery.
~ W094/07496 21~117 PCr/US93/09152 It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in ~nim~l.c, ~lefe~dbly m~mm~l~, especially in hllm~n~. It is ano~er purpose of this invention to prepare novel compounds which more 5 selectively inhibit oxytocin. It is still another purpose of this invention toprovide a method of antagonizing the functions of oxytocin in disease states in m~mm~l~. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dys~nenorrhea by antagonizing oxytocin.
It has now been found that compounds of the present invention are antagonists of oxytocin and bind to the oxytocin receptor. VVhen the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or ph~rm~cologic effects. These compounds 15 are useful in the treatment and prevention of oxytocin-related disorders of ~nim~ , preferably m~mm~l~ and especially hllm~n~. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Caesarean delivery.
20 SUMMARY OF THE ~VENTION
The compounds and their pharmaceutically acceptable salts and esters of the present invention are those of the general structural formlll7~:
X-Y-Z-Rl, wherein xis WO 94/07496 PCI /US93/09152 ~
21~3117 ¢~W F~
I
W is hydrogen or acetate;
Y is -CO-, -SO2- -CO(CH2)m- or-(CH2)m-;
Z is an optionar substituent that, when present, is one or more of N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m- or-CHCHOH-;
R is hydrogen, Cl 5 aLkyl or Cl 5 alkoxycarbonylamino, quinuclidinylaminocarbonylamino;
R1 is -CH3, -CH(CH3)2, C1 5 alkoxycarbonyl, ~ W094/07496 21~3117 PCI~/US93/09152 R3 ' ~ , ~0 .
~\~3, ~ --~ ~ R3 ~ ~ R2 ~;3 , ~, ~13 ~,~ R2 _~ ~ 2 ~ ~(CH2)m~C 3 <r/~H3 20 -NR4R5 or-NCOR6;
R2 is hydrogen, hydroxy, carboxyl, acetyl, nitro, cis or trand oximino, halogen, mono-, di- or tri-Cl 3 aL~cyl, spirocyclic indenyl, 25 N-~iruilldanepiperidinyl, O-R where R is as defined above, O-Het where Het is imidazole or benzimidazole or azimidobenzene, or where R2 is fur~er defined as -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7~
-(CH2)m-NR8R9, -(CH2)m-NHCo-(cH2)mR7, -(CH2)~,-NHCo-cHR7R7, -(CH2)m-NHCo-CH=CHR7, -(CH2)m-CO-O -R7, -(CH2)m-CO-O-3 (CH2)mR7, -(CH2)~m-C0-0-CHR7R7, -(CH)m-Co-o-cH=cHR7~
-NHS02R-where R is as de~ned above, NHSo2R7, -(CH2)m-O-R10, -S02R10, CoRl 1 WO 94/07496 PCI`/US93/09152~
-CONH(CH2)m~ -(CH2)m~ HO~) ~SO2~ NH2 CH3 . or (CH2)m 2~cH
o or one to two substituents selected from the group consisting of /~¢~ or 15 R3 is one or two of hydrogen, hydroxyl or Cl S aLkyl;
with the proviso that when R1 is cyclohexyl, then R2 and R3 are limited to being hydroxyl or Cl 5 aLkyl;
20 R4 is hydrogen, C1 5 aLkyl, or C6 10 cycloalkyl;
R5 is hydrogen or acetyl;
R6 is SO2~ 3 or ~ SOz~ 3;
R7is ~ w094/07496 21~311 7 PCr/US93/09152 ~,~Rl2 ~NH ~(CH2)m ~C3 -(CH2)m \=~ Rl2 ~ ~(CH2)m N , NH ~
~(CH2)m--~ \> -(CH2)m--~H . -(cH2)m~1, -(C~ ~ -(CH2)m~
CH CH~,~ -(CH2)m ~0--1<CH
-(CH2) ~ <C ~(CH2)m ~ ~~CH2)m ~cH2 hydrogen, Cl 4 aLkyl, NS02R1 2 or NHO-C1 -4 alkyl;
R8 is hydrogen or C1 5 alkyl;
R9 is hydrogen or Cl 5 aLkyl;
3 0 R l is -CH3, W O 94/07496 PC~r/US93/09lS2 ~
TOCOLYTIC OXYTOCIN RECEPTOR ANTAGONISTS
FIELD OF THE ~VENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their m~mlf~cture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy. The aforementioned pharmacologic activities are useful in the treatment of m~mm~l~. More specifically, ~e compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Caesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
BACKGROUND OF THE INVENTION
In the field of obstetrics, one of the most i~nportant problems is the m~n~gement of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a le~clin~ cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents ~at are cullelllly in use include ~2-adrenergic agonists, m~gnesium sulfate and ethanol. Ritodrine, the le~(lin~ ~2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other ~2-adrenergic agonists, including ~ b~ line and albuterol have side effects simil~r to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular tr~n~mi~sion, respiratory depression and cardiac arrest, thus m~kinp this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature 21~3117 labor, but it does not produce a corresponding reduction in the inciden ce of fetal respiratory distress that ~tlmini~tration of ritodrine does.
It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has acc1lm~ ted 5 to strongly suggest that the hormone oxytocln may be a physiological initi~tor of labor in several m~mm~ n species including hllm~n~.
Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prost~ n-lin~ from the uterine endometriumldecidua. These prost~gl~n~lin~ may, in addition, be important in the cervical ripening process. By these mech~ni~m~, the process of labor (term and preterm) is initi~ted by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This "up-regulation" of oxytocin receptors and 5 enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prost~gl~nclin synthesis) effects of oxytocin on the uterus. A selective oxytocin blocker, or antagonist, would likely be more efficacious for treating preterm labor 20 than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few, if any, side effects.
The compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic 25 pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometriumL. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating 3 dysmenorrhea then current regimens. An additional use for the present invention is for the stoppage of labor preparatory to Caesarean delivery.
~ W094/07496 21~117 PCr/US93/09152 It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in ~nim~l.c, ~lefe~dbly m~mm~l~, especially in hllm~n~. It is ano~er purpose of this invention to prepare novel compounds which more 5 selectively inhibit oxytocin. It is still another purpose of this invention toprovide a method of antagonizing the functions of oxytocin in disease states in m~mm~l~. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dys~nenorrhea by antagonizing oxytocin.
It has now been found that compounds of the present invention are antagonists of oxytocin and bind to the oxytocin receptor. VVhen the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or ph~rm~cologic effects. These compounds 15 are useful in the treatment and prevention of oxytocin-related disorders of ~nim~ , preferably m~mm~l~ and especially hllm~n~. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Caesarean delivery.
20 SUMMARY OF THE ~VENTION
The compounds and their pharmaceutically acceptable salts and esters of the present invention are those of the general structural formlll7~:
X-Y-Z-Rl, wherein xis WO 94/07496 PCI /US93/09152 ~
21~3117 ¢~W F~
I
W is hydrogen or acetate;
Y is -CO-, -SO2- -CO(CH2)m- or-(CH2)m-;
Z is an optionar substituent that, when present, is one or more of N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m- or-CHCHOH-;
R is hydrogen, Cl 5 aLkyl or Cl 5 alkoxycarbonylamino, quinuclidinylaminocarbonylamino;
R1 is -CH3, -CH(CH3)2, C1 5 alkoxycarbonyl, ~ W094/07496 21~3117 PCI~/US93/09152 R3 ' ~ , ~0 .
~\~3, ~ --~ ~ R3 ~ ~ R2 ~;3 , ~, ~13 ~,~ R2 _~ ~ 2 ~ ~(CH2)m~C 3 <r/~H3 20 -NR4R5 or-NCOR6;
R2 is hydrogen, hydroxy, carboxyl, acetyl, nitro, cis or trand oximino, halogen, mono-, di- or tri-Cl 3 aL~cyl, spirocyclic indenyl, 25 N-~iruilldanepiperidinyl, O-R where R is as defined above, O-Het where Het is imidazole or benzimidazole or azimidobenzene, or where R2 is fur~er defined as -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7~
-(CH2)m-NR8R9, -(CH2)m-NHCo-(cH2)mR7, -(CH2)~,-NHCo-cHR7R7, -(CH2)m-NHCo-CH=CHR7, -(CH2)m-CO-O -R7, -(CH2)m-CO-O-3 (CH2)mR7, -(CH2)~m-C0-0-CHR7R7, -(CH)m-Co-o-cH=cHR7~
-NHS02R-where R is as de~ned above, NHSo2R7, -(CH2)m-O-R10, -S02R10, CoRl 1 WO 94/07496 PCI`/US93/09152~
-CONH(CH2)m~ -(CH2)m~ HO~) ~SO2~ NH2 CH3 . or (CH2)m 2~cH
o or one to two substituents selected from the group consisting of /~¢~ or 15 R3 is one or two of hydrogen, hydroxyl or Cl S aLkyl;
with the proviso that when R1 is cyclohexyl, then R2 and R3 are limited to being hydroxyl or Cl 5 aLkyl;
20 R4 is hydrogen, C1 5 aLkyl, or C6 10 cycloalkyl;
R5 is hydrogen or acetyl;
R6 is SO2~ 3 or ~ SOz~ 3;
R7is ~ w094/07496 21~311 7 PCr/US93/09152 ~,~Rl2 ~NH ~(CH2)m ~C3 -(CH2)m \=~ Rl2 ~ ~(CH2)m N , NH ~
~(CH2)m--~ \> -(CH2)m--~H . -(cH2)m~1, -(C~ ~ -(CH2)m~
CH CH~,~ -(CH2)m ~0--1<CH
-(CH2) ~ <C ~(CH2)m ~ ~~CH2)m ~cH2 hydrogen, Cl 4 aLkyl, NS02R1 2 or NHO-C1 -4 alkyl;
R8 is hydrogen or C1 5 alkyl;
R9 is hydrogen or Cl 5 aLkyl;
3 0 R l is -CH3, W O 94/07496 PC~r/US93/09lS2 ~
2~3~l~
.
~CH3 CH2~cH3 CH=CH~CH3 ~ ~ CH2C
N~
Rl 1 is -CH3, H
--CH=CH~ (CH2)m~, ~(CH2)m N
N--N N=\
~(CH ) ~N~> or ~CH=CH~
R12 is hydrogen, C1 5 alkyl or Cl 5 alkoxy; and 25 m is an integer of from O to 5;
~W
with the proviso ~at when X is N
~ WO 94/07496 2 1 ~ 31 1 7 PCl/US93/0915' g and when Rl is disubstituted phenyl when the phenyl substit--ent~ are any of hydroxyl, carboxyl, nitro, halogen, mono-, di- or tri-Cl 3 alkyl, Cl 5 aL~coxy; or when Rl is pyridyl; or when Rl is -CH3 or -CH(CH3)2; or when Rl is unsubstituted bicyclo loweralkyl of 9 carbons or unsubstituted 5 or substituted cyclohexyl and the substituent is hydroxyl; then Y is -(CH2)m- where m has a value of from 1 to 5.
Salts and esters encompassed within the term "ph~ ceutically acceptable salts and esters" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
Acetate Lactobionate Benzenesulfonate Laurate Benzoate Malate Bicarbonate Maleate Bisulfate Mandelate Bitartrate Mesylate Borate Methylbromide 2 0 Bromide Methylnitrate Calcium Edetate Methylsulfate Camsylate Mucate Carbonate Napsylate Chloride Nitrate 2 5 Clav~ n~te N-methylglllc~mine Citrate ammonium salt Dihydrochloride Oleate Edetate Oxalate - Edisylate Pamoate (Embonate)
.
~CH3 CH2~cH3 CH=CH~CH3 ~ ~ CH2C
N~
Rl 1 is -CH3, H
--CH=CH~ (CH2)m~, ~(CH2)m N
N--N N=\
~(CH ) ~N~> or ~CH=CH~
R12 is hydrogen, C1 5 alkyl or Cl 5 alkoxy; and 25 m is an integer of from O to 5;
~W
with the proviso ~at when X is N
~ WO 94/07496 2 1 ~ 31 1 7 PCl/US93/0915' g and when Rl is disubstituted phenyl when the phenyl substit--ent~ are any of hydroxyl, carboxyl, nitro, halogen, mono-, di- or tri-Cl 3 alkyl, Cl 5 aL~coxy; or when Rl is pyridyl; or when Rl is -CH3 or -CH(CH3)2; or when Rl is unsubstituted bicyclo loweralkyl of 9 carbons or unsubstituted 5 or substituted cyclohexyl and the substituent is hydroxyl; then Y is -(CH2)m- where m has a value of from 1 to 5.
Salts and esters encompassed within the term "ph~ ceutically acceptable salts and esters" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
Acetate Lactobionate Benzenesulfonate Laurate Benzoate Malate Bicarbonate Maleate Bisulfate Mandelate Bitartrate Mesylate Borate Methylbromide 2 0 Bromide Methylnitrate Calcium Edetate Methylsulfate Camsylate Mucate Carbonate Napsylate Chloride Nitrate 2 5 Clav~ n~te N-methylglllc~mine Citrate ammonium salt Dihydrochloride Oleate Edetate Oxalate - Edisylate Pamoate (Embonate)
3 Estolate P~lmit~te - Esylate Pantothenate Fumarate Phosphate/diphosphate WO 94/07496 PCl /US93/09152 ~
2~4~ Ll~
-Gluceptate Polygalacturonate Gluconate Salicylate Glllt~m~te Stearate Glycollylars~nil~te Sulfate Hexylresorcinate Subac~tate Hydrabamine Succinate Hydrobromide Tannate Hydrochloride Tartrate Hydroxynaphthoate Teoclate Iodide Tosylate Isothionate Triethiodide Lactate Valerate The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, ~nim~l or hllm~n that is being sought by a researcher or clinician.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range.
The term "alkenyl" shall mean straight or branched chain aLkenes with one or more degrees of lm.~ lration at any position on the chain, of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes with one or more degrees of lmc~lllration at any position on ~e chain, of two to ten total carbon atoms, or any number within ~is range.
The term ""aryl" shall mean phenyl, naphthyl or fluorenyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms.
Whenever the terrns "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy) they shall be inte~ ed as including those limitations given above for "alkyl" and ~ WO94/07496 21~3117 PCl/US93/09152 "aryl". Designated numbers of carbon atoms (e.g. C1 1o) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "oxo" shall refer to the substituent =0.
The term "azimidobenzene" (also known as benzotriazole) shall refer to the moiety 1 o N~ ~
The term "spirocyclic indenyl" shall refer to the moiety 1~1 The term "halogen" shall include iodine, br~ e, chlorine and fluorine.
The term "preterm labor" shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or ~ e of the membranes.
The term "dysmenorrhea" shall mean painful menstruation.
The term "Caesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.
WO94/07496~ 21~311'Z PCl/US93/09152~
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
The ability of the compounds o~ ~ormula I to antagonize 5 oxytocin makes these compounds useful as ph~ cologic agents for m~mm~l~, especially for hllm~n~, for the treatment and prevention of disorders wherein oxytocin may be involved. F.x~mples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean 1 delivery-Because of the known relationship of vasopressin to oxytocin,the compounds of the present invention are also useful as vasopressin antagonists. Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their 15 use as diuretics and their use in congestive heart failure.
The compounds of the present invention can be ~lmini~tered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and em~ ions. Likewise, they may also be 20 ?~flmini~tered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the ph~ ceutical arts. An effect*e but non-toxic amount of the compound desired can be employed as a tocolytic agent.
The dosage regimen l~tili7in~ the compounds of the present 25 invention is selected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of ~(lmini~tration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily 30 determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
2I~311 7 WO 94/07496 - PCr/US93/09152 Oral dosages of the present invention, when used for the indicated effects, will range between about 0.3-6.0 gm/day orally.
Intravenously, the most preferred doses will range from 0.1 to about 10 mg/mimlt~ during a constant rate infusion. Advantageously, compounds of 5 the present invention may be ~lministered in a single daily dose, or the total daily dosage may be ~(lmini~tered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be ~1mini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
To be ~lmini~tered in the form of a transdermal delivery system, the dosage a~mini~tration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein 15 described in detail can form the active ingredient, and are typically ~lmini~tered in ~ ix~ e with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of ~lmini~tration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with 20 conventional ph~ ceutical practices.
For instance, for oral ~lmini~tration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic ph~m~ceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, 25 lubricants, disintegrating agents and coloring agents can also be incorporated into the mix~lre. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tr~g~r~ntl or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
3 Lubricants used in these dosage forms include sodium oleate, sodium stearate, m~gnesium stearate, sodium benzoate, sodium acetate, sodium wo 94,07496 2 1 ~3 11~ PCI/US93/09152~
chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, 7~nth~n gum and the like.
The compounds of the present invention can also be ~lmini~tered in the form of liposome delivery systems, such as small 5 lmil~mellar vesicles, large lmil~mellar vesicles and mllltil~mellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyl~mine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the o compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with 15 palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic 20 block copolymers of hydrogels.
The compounds of formula I can be prepared readily according to ~e following reaction Schemes (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis 25 procedures. ~ these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, 3 however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples fur~er illustrate details for ~ WO 94/07496 2 1 ~ 3 1 1 7 PCr/US93/0915' the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless 5 noted other~,vise.
WO 94/07496 PCI/US93/09~52 ~
2~3l~l Cl-CO CH2~R
N EDC/HBT/DMF or BOP
R~
/ ~+~X-CO-CI ~X
~ R3/`3~ j2N~o-co~
N ~ /~(H)n N (WhereX=N,OorS) X = O, N, S, CH2 o~O
n=1,2 ~ wo 94/07496 2 1 ~ 3 1 1 7 PCl /US93/09152 SCHFMF ?
N Hydro9enation N
O~CH2 ~O~cH2 ¢~ ~
N2 / ~ NH2 [OH--]/
~ / BOP / \ BOP
20 ~C~ ~ ~
+ HOOCcH2~ NH2 NHCOR
H
WO 94/07496 PCI`/US93/0915'' 2~43~
SCHEM~ 3 CH Where W is a ~ 3 ~W~W~ suitable leaving group NH2 N and Z is a protecting z group such as BOC or CBZ
[~ N~l Deprotection [~CH3 ~/ N~z / ~R/ N~H
3// R~
/ Cl-CO~/,~
~CI 13 / R' R O~ ~N~
~ WO 94/07496 2 1 4 3 1 1 7 PCI~/US93/09152 SCHFME 4 ~=~/R
Cl-CO-CH2~
s ~CH3 or HOOCCH2~R
EDC/HBT/DMF or BOP
~ Cl CO~,~ ¢N~CH3 l 5 I~CH3 X-CO-CI~ o X
~ ~ H
Z H3CJ~ ~/)n R3 ~ ~ (Where X= N,O or S) X=O,N,S,CH2 n=1,2 ~
WO 94/07496 PCl/lJS93/09152~
2~3il~
Abbreviations used in the Examples are as follows:
EDC = l-ethyl-3-(3-dimethylaminQpropyl)carbodiimide hydrochloride .
BOC = tert-butoxycarbonyl TEA = triethyl~mine DIEA = diisopropylethyl~mine BOP = benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate THF = tetrahydrofuran DMF = dimethylformamide LAH = lithium all-minllm hydride TFA = trifluoroacetic acid HPLC Method A = 15 min. linear gradient 95:5 A:B to 0:100 A:B
A - H20 cont~inin~ 0.1% by vol. TFA
B = CH3CN cont~inin~ 0.1% by vol. TFA
2.0 mL/min flow rate 12 cm Clg reverse phase column W detection (215 nm) TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.
~ wo 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 s 0~
0~
70 mg (0.316 mmol) of spiro(lH-indene-1,4'-piperidine HC1) was dissolved in 3 ml DMF and the solution treated with 52.5 mg (0.347 mmol) of 4-aminophenyl acetic acid followed by 161 mg (0.363 mmol) of benzotriazol-1-yl-oxy(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 142 ~11 15 (0 794 mmol) of diisopropylethyl~mine and the mixture stirred at 25 for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2S04, filtered 20 and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (1:1 of ethyl acetate: CH2Cl2) gave the title compound as a white foam (41 mg, 40.6% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: 318.402.
m.p.: 60-87C (sinter) HPLC: 96.3%
PMR: Consistent with structure plus ether and water M.S.: M+H = 319 (FAB).
- TLC: Rf = 0.34, Silica GF (1:1 of EtOAc: CH2Cl2).
CHN: Calc'd as C21H22N2O-0.05 C4H100-0.30 H20 (F.W. = 327.532):
W O 94/07496 43~ PC~r/US93/09152 C, 77.74; H, 7.11; N, 8.55.
Found: C, 77.83; H, 6.80; N, 8.23.
.~ , .
~ ¢~NH CH3 l.lgm (3.45 mmol) of the product of Fx~mrle 1 was dissolved in 15 ml of CH2C12 and ~e solution treated with 0.27 ml (3.80 rnrnol) of acetyl chloride. The pH was adjusted to 9.5 with 0.55 ml (3.82 mmol) of triethyl~mine and the mixture stirred at 25C for 1 hour.
Flash chromatography of ~e reaction mixture directly on silica gel (3:1 of ethyl acetate: CH2C12) gave the title compound as a crystalline solid (992 mg, 79.3% yield) from ethyl acetate.
M.W. 360.438.
m.p.: 217-9C.
HPLC: 99.5%
PMR: Consistent with structure.
M.S.: M+H=361(PAB).
TLC: Rf = 0.31, Silica GF (3:1 of ethyl acetate: CH2C12).
CHN: Calc'd as C23H24N202:
C, 76.64; H, 6.71; N, 7.77.
Found: C, 76.26; H, 6.80; N, 7.76.
WO 94/07496 - PClr/US93/09152 0~
125 mg (0.564 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF and the solution treated with 112 mg (0.620 mmol) of o-nitrophenyl acetic acid followed by 286 mg (0.649 mmol) of benzotriazol-l-yl-oxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent). The pH of the solution was adjusted to 9.5 with 307 ,ul (1.75 mmol) of diisopropyl ethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with H20 and extracted with ethyl acetate (3x). The organic extracts were 20 combined, washed wi~ water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dIyness in vacuo. Flash chromatography of the crude product on silica gel (3% Et2O in CH2Cl2) gave 155.7 mg (79.4% yield) of the title compound as a white foam after evaporation in vacuo.
M.W.: 348.386.
m.p.: 60-75C (sinter).
HPLC: 93.4%.
PMR: Consistent with structure plus water.
M.S.: M+H = 349.2 (FAB).
TLC: Rf = 0.29, Silica GF (4% Et2O in CH2C12).
CHN: Calc'd as C21H20N2O3-0.30 H20 (~.W. = 353.8):
C, 71.28; H, 5.87; N, 7.92.
WO 94/07496 21 ~3 11~ PCI/US93/09152~
Found: C, 71.35; H, 5.64; N, 7.91.
FXAMPLE~
., H o ' 0~~
250 mg (1.13 mmol) spiro(lH-indene-1,4'-piperidine) hydro-chloride was dissolved in 10 ml DMF and the solution treated with 15 350 mg (1.24 mmol) of 2-(t-butyloxyaminomethyl)-phenylacetic acid followed by 575 mg (1.30 mmol) of benzotriazol-l-yloxytris (dimethyl-amino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (13% Et2O in CH2C12) gave the title compound 25 isolated as a crystalline solid (285 mg, 56% yield) from diethyl ether.
M.V.: 448.542.
m.p.: 165-7C.
HPLC: 97.2%.
30 PMR: Consistent wi~ structure plus ether.
M.S.: M+H + Thioglycerol (M.W. = 108) = 5573 (FAB).
TLC: Rf = 0.48, Silica GF (20% ET2O in CH2C12)-~WO 94/07496 2 1 ~ 3 1 1 7 PCI`/US93/09152 CHN: Calc'd as C27H32N204-0.10 C4HloO (F.W. = 455.954) C, 72.17; H, 7.30; N, 6.14.
Found: C, 72.12; H,7.33; N, 6.29.
s EXAMPLE S
~ 1 ~N
O ~ N O
H
250 mg (1.13 mmol) of spiro(lH-indene-1,4'-piperidene) hydrochloride was dissolved in 10 ml DMF and the solution treated with 350 mg (1.24 mmol) of 3-(t-butyloxyaminomethyl)-phenyl acetic acid followed by 575 mg (1.30 mmol) of benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the 20 solution was adjusted to 9.5 with 550 ,ul (3.14 mmol) of diisopropyl-ethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washedl with water (lx), dried over Na2S04, filtered, and 25 stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (20% Et2O in CH2Cl2) gave the title compound as a white foam (328 mg, 65.0% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: 448.542.
30 m.p.: SS-72C (sinter).
HPLC: 99.6%
PMR: Consistent with structure plus water.
W094/07496 2~43l~rt PCI/US93/09152 M.S.: M+H + Thioglycerol (M.W. - 108) = 557.6 (FAB).
TLC: Rf = 0.52, Silica GF (25% Et2O in Ch2cl2).
CHN: Calc'd as C27H32N2O4-0 15 H20 (F.W. = 451.269):
C, 71.86; H, 7.21; `-N, 6.21.
Found: C, 71.83; H, 7.09; N, 6.45.
l o ~>~ ,~¢N>
70 mg (0.220 mmol) of the product of Fx~mple 1 was dissolved in 5 ml DMF and the solution treated with 39.3 mg (0.242 mmol) of imidazole-4-acetic acid-hydrocloride followed by 32.7 mg (0.242 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 46.4 mg (0.242 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC). The pH was adjusted to 9.5 with triethyl~mine and the mixture stirred at 25C
or 4 hours.
DMF was removed in vacuo and the crude residue treated with water and extracted with e~yl acetate (3x). The organic extracts were combined, washed with water (1x), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2C12:MeOH: Conc NH40H) gave the title compound as a white solid (50.8 mg, 54.2% yield) after evaporation in vacuo and trituration with ether.
M.W.: 426.50.
m.p.: 104-36C (sinter).
21~3117 HPLC: 99.3%
PMR: Consistent with structure plus ether, CH2C12, and water.
M.S.: M+H + 427.1 (FAB).
TLC: Rf = 0.32, Silica GF (80:10:1 of CH2Cl2: MeOH:
Conc. NH40H).
CHN: Calc'd a C26H26N4)2-0.10 CH2C12-0.10:
C4H1oO-0.50 H20 (F.W. = 451.212):
C, 70.53; H, 6.26; N, 12.42.
Found: C, 70.56; H, 6.04; N, 12.64.
~ NH2 85 mg (0.267 mmol) of the product of Example 1 was dissolved in S ml DMF and the solution treated with 72.3 mg (0.294 mmol) of N-t-butyloxycarbonyl-L-glllt~mine followed by 39.7 mg (0.294 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 56.3 mg (0.294 mmol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The 25 pH was adjusted to 9.5 with 55 ,ul (0.395 mmol) of triethyl~mine (Et3N) and the ~ Ul~ stirred at 25C for 1.5 hours.
A second portion of 72.3 mg (0.294 mmol) of N-t-butyloxy-carbonyl-L-~ t~mine, 39.7 mg (0.294 mmol) of H B T, 56.3 mg (0.294 mmol) of EDC and 55 ,ul (0.395 mmol) of Et3N was added and the 30 mixture stirred at 25C for 18 hours.
DMF was removed in vacuo and the residue treated with H20 and extracted with ethyl acetate (3x). The organic extracts were com-WO 94/07496~ 3~ PCr/US93/0915 bined, washed with water (lx), brine (lx), dried over Na2S04, filtered and stripped to dryness in vacuo. Flash chromatography of ~e crude product on silica gel (6% MeOH in CH2C12) ga~ the title compound as a white solid (57.4 mg, 39.3% yiel~d) after evaporation in vacuo and 5 trituration with ether.
M.W.: 546.646.
m.p.: 104-47C (sinter).
HPLC: 99.1 %.
PMR: Consistent with structure plus water and ether.
M.S.: M+H = 547 (FAB).
TLC: Rf = 0.18, Silica GF (4% MeOH in CH2C12).
CHN: Calc'd as C31H3gN4O5-0.10 C4HloO-0.75 H20 (F.W. = 5657.597):
C, 66.44; H, 7.19; N, 9.87.
Found: C, 66.42; H, 6.98; N, 10.04.
N ~Br O~J
75 mg (0.338 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF and the solution treated with 80.0 mg (0.372 mmol) of 4-bromophenyl acetic acid followed by 171.9 mg 30 (0.389 mmol) of benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP Reagent). The pH of ~e solution was adjusted ~ WO94/07496 21~3117 PCI/US93/09152 to 9.5 with 125 ml (0.710 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were 5 combined, washed with water (lx), brine (lx), dried over Na2SO4, ~1ltered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (5% Et20 in CH2Cl2) gave the title compound as a white foam (30 mg, 23.3% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: = 382.282.
m.p.: 44-58C (sinter).
HPLC: 99.5%.
PMR: Consistent with structure plus water.
M.S.: M+H = 382.1/384.1 at 1/1 (FAB).
TLC: Rf = 0.44, Silica GF (6% Et2O in ch2c12)-CHN: Calc'd as C21H20BrNo-o.4o H2O (F.W. = 389.513):
C, 64.75; H, 5.38; N, 3.60.
Found: C, 64.51; H, 5.06; N, 3.60.
~NH~ >
375 mg (1.18 mmol) of the product of Example 1 was dissolved in 10 ml DMF and the solution treated with 179 mg (1.30 mmol) of urocanic acid followed by 175 ml (1.29 mmol of 1-hydroxybenzo-wo 94/07496 ~ ~3~ ~'1 PCI`/US93/0915 triazole hydrate (HBT) and 248.5 mg (1.30 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC). The pH of the solution was adjusted to 9.5 with 414 ,ul (0.298 mmol) of triethyl~mine (Et3N) and the reaction stirred at 25C for~6~hours.
A second portion consisting of 179 mg (1.30 rnmol) of urocanic acid, 175 mg (1.29 mmol) of HBT, 249 (1.30 mmol) of EDC and 414 ~11 (0.298 mmol) of Et3N was added and the reaction stirred at 25C
for 18 hours.
DMP was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (1x), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2Cl2: MeOH: Conc. NH40H) gave the title compound as a crystalline solid (106 mg, 20.5% yield) from ethyl acetate.
M.W.: = 438.51.
m.p.: 170-85C (Physical Change); 228-30C (melt).
HPLC: 99.0%.
PMR: Consistent with structure plus water.
2 0 M.S.: M+H = 439 (FAB).
TLC: Rf = 0.36, silica GF (80:10:1 of CH2Cl2:
MeOH: Conc. NH40H).
CHN: Calc'd as C27H26N402-0.95 H20 (F.W.455.468):
C, 71.17; H, 6.17; N, 12.30.
25 Found: C, 71.05; H, 5.78; N, 11.91.
WO 94/07496 PCl /US93/09152 ., . 0~0>
60 mg (0.271 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 4 ml DMF and the solution treated with 53.7 mg (0.298 mmol) of 3,4-methylenedioxy phenyl acetic acid followed by 137.8 mg (0.312 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 wi~ 100,ul (0.569 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed wi~ water (lx), brine (lx), dried over Na2SO4, fîltered 20 and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (6% Et2O in CH2Cl2) gave the title compound as a c~ystalline solid (32.4 mg, 34.3% yield) from ether.
M.W.: 347.396.
m.p.: 123-5C.
HPLC: 99.4%
PMR: Consistent with structure plus water.
M.S.: M+H = 348.1 (FAB).
TLC: Rf = 0.30, Silica GF (6% Et2O in Ch2cl2) - CHN: Calc'd as C22H21NO3-0.15 H2O (F.W. = 350.119):
C, 75.47; H, 6.13; N, 4.00.
Found: C, 75.51; H, 5.79; N, 4.01.
WO 94/07496 PCr/US93/0915~
3~
EXAMPLE 11 ~;
N
300 mg (1.35 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 10 ml DMF and the solution treated with 341 mg (1.49 mmol) of p-bromoethyl phenyl acetic acid followed by 687 15 mg (1.55 mmol) of benzotriazol-l-yloxy(dimethylamino) phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 769 ~11 (4.39 mml) of diisopropylethyl~mine and the mixtllre stirred at 25C for 18 hours.
DMF was removed in vacuo and the crude residue treated with 20 water and extracted with ethyl acetate (3x). The oganic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (12% Et2O in CH2Cl2) gave the title compound as a white foam (318 mg, 59.3% yield) upon coevaporation with 25 ether (3x) in vacuo.
M.W.: 450.52.
m.p.: 50-64C.
HPLC: 94.9%.
PMR: Consistent with structure plus water.
M.S.: M+H = 451 (FAB).
TLC: Rf = 0.27, silica GF (15% Et2O in CH2C12)-.
WO 94/07496 2 1 ~ 3 1 ~ 7 PCI/US93/09152 CHN: Calc'd as C28H26N402-1.30 H20 (F.W. = 473.965):
C, 70.95; H, 6.08; N, 11.82.
Found: C,70.98; H, 5.81; N, 12.00.
~ N~N>
60 mg (0.188 mmol) of the product of Example 1 was 15 dissolved in 3 ml DMF and the solution treated with 36.6 mg (0.226 mmol) of benzoimidazole-5-carboxylic acid followed by 30.5 mg (0.226 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 43.3 mg (0.226 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH was adjusted to 9.5 with 63.0 ~1 (0.453 mmol) of triethyl~mine and the 20 mixture stirred at 25C for 20 hours.
A second portion consisting of 18.3 mg (0.226 mmol) of benzoimidazole-5-carboxylic acid, 15.3 mg (0.113 mmol) HBT, 21.7 mg (0.113 mmol) EDC and 31.5 ~11 (0.227 mmol) of triethyl~mine was added and the reaction stirred at 25C for 6 hours.
DMF was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2Cl2:MeOH:Conc. NH40H) gave the title compound as a crystalline solid (51.5 mg, 59.1% yield) from ethyl acetate.
W094/07496 ~ PCr/lJS93/0915 M.W.: 462.53.
m.p.: 212-6C.
HPLC: 98.8%. ~ .
PMR: Consistent with structure.
M.S.: M+H=463 (FAB).
TLC: Rf = 0.34, silica GF (80:10:1 of C12:MeOH:Conc NH4OH).
CHN: Calc'd as C29H26N402: (m.w. - 462.53):
C, 75.30; H, 5.67; N, 12.11.
Found: C, 75.18; H, 5.66; N, 12.06.
~ I
O~N CH3 ~f CH3 O
100 mg (0.451 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF N-ethoxycarbonyl-a-(4-Acet~miclophenyl)-glycine followed by 229 mg (0.519 mrnol) of 2 5 benzotriazol- 1 -yl-oxytris(dimethylamino)phosphonium hexafluoro-phosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 166 ~11 (0.947 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hours.
DMF was removed in vacuo and the crude residue treated with 30 water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude WO 94/07496 - PCTtUS93/091~2 product on silica gel (3% MeOH in CH2Cl2) gave the title compound isolated as a crystalline solid (139 mg, 68.8% yield) from ether.
M.W.: 447.516.
m.p.: 216-8C.
HPLC: 98.1 %.
PMR: Consistent with structure.
M.S.: M+H=448.1 (FAB).
TLC: Rf = 0.27, silica GF (4% MeOH in CH2Cl2).
CHN: Calc'd as C26H29N304 (F.W. - 447.516):
C, 69.78; H, 6.53; N, 9.39.
Found: C, 69.67; H, 6.51; N, 9.55.
~ H
74.4 mg (0.170 mmol) of the product of Example 9 was dissolved in 10 ml of absolute ethanol, treated with 15 mg 10% Pd on C
25 under a nitrogen atmosphere, and hydrogenated at 60 psi for 3 hours. The mixhlre was filtered through SoLka Floc~ to remove catalyst and the filter pad was washed thoroughly with fresh absolute ethanol. The filtrate was evaporated to dryness in vacuo and the residue was flash chromatographed on silica gel (60:10:1 of CH2Cl2:MeOH:H2O:HoAc). The product 30 fractions were combined, stripped to dryness in vacuo, and the residue treated with dilute NaHCO3(aq) and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (1x), dried over WO 94/07496 PCl /US93/09~5~
~43~
Na2SO4, filtered and stripped to dryness in vacuo. The residue was coevaporated with ether (3x), then tri~rated with ether and filtered to give the title compound as a white solid (44.8 mg, 59.7% yield).
M.W.: 442.542.
m.p.: 89-128C.
HPLC: 99.6%.
PMR: Consistent wi~ structure plus e~er, ethyl acetate and water.
M.S.: M+H=443.1 (FAB).
o TLC: Rf = 0.29, silica GF (60:10:1:1 of CH2Cl2:MeOH:H2O:HoAc).
CHN: Calc'd as C27H30N4O2-0.15 C4HloO-O.10 C4HgO2-0.35 H20:
C, 71.74; H,7.10; N, 11.95.
Found: C, 71.68; H,7.05; N, 11.75.
~3~ N~
2s 50 mg (0.157 mmol) of the product of F~mple 1 was dissolved in 2 ml DMF and the solution treated with 27.8 mg (0.173 mmol) of indole-5-carboxylic acid followed by 23.3 mg (0.173 mmol of l-hydroxybenzotriazole hydrate (HBT) and 33.1 mg (0.173 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC).
The pH of the solution was adjusted to 9.5 with 49 ~1 (0.350 mmol) of triethyl~mine and the reaction stirred at 25C for 1 hour.
WO 94/07496 2 1 4 3 1 1 7 PCr/US93/09152 A second portion consisting of 13.0 mg (0.081 mmol) of indole-5-carboxylic acid, 12.0 mg (0.089 mmol) HBT, 15.0 mg (0.078 mmol) EDC, and 22.1 lul (0.159 mmol) of triethyl~min~ was added and ~e reaction stirred at 25C for 1 hour. DMF was removed in vacuo and the 5 residue treated with water and extracted with ethyl acetate (3x). The organic layers were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (230:10:1 of CH2Cl2:MeOH:Conc. NH40H) gave the title compound as an off-white solid (30.0 mg, 37.6% yield) upon trituration with ethyl acetate.
M.W.: 461.54.
m.p.: 241-3C.
HPLC: 97.7%.
PMR: Consistent with structure plus water.
M.S.: M+H=462 (FAB).
TLC: Rf = 0.25, silica GF (200:10:1 of CH2Cl2:MeOH:conc.
NH4OH) CHN: Calc'd as C30H27N302-0.75 H2O. (F.W.=492.701):
C, 75.08; H, 6.16; N, 8.53.
Found: C, 74.97; H,. 5.80; N, 8.47.
~XAMPLE 16 ~ O
~HN ~cN N
~43~
55 mg (0.173 mmol) of the product of Example 1 was dissolved in 2 ml DMF and the solution was treated with 33.9 mg (0.208 mmol) of benzotriazole-5-carboxylic ac~d~followed by 28.1 mg (0.208 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 39.9 mg (0.208 s mmol of l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH of the solution was adjusted to 9.5 with 66.6 ~1 (0.478 mmol) of triethylamine and the reaction stirred at 25C for 18 hours.
DMF was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped in dryness in vacuo. Flash chromatography of the crude product on silica gel (88:10:1 of CH2C12:MeOH: Conc. NH40H) gave the title compound as a crystalline solid (39.8 mg, 49.8% yield from ethyl acetate.
M.W.: 463.52.
m.p.: 229-32C.
HPLC: 99.6%
PMR: Consistent with structure plus ethyl acetate.
M.S.: M+H=464 (FAB).
TLC: Rf = 0.33, silica GF (80:10:1 of CH2C12:MeOH:Conc.
NH40H) CHN: Calc'd as C2gH25N5O2-0.05 C4H802 (F.W. = 467.948):
C, 72.38; H, 5.47; N, 14.97.
Found: C, 72.39; H, 5.33; N, 14.92.
~ WO 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 ~ ~ ~[OCH
55.0 mg (0.173 mmol) of the product of F.x~mrle 1 was dissolved in 3 ml CH2C12 and the solution treated with 37.9 mg (0.189 mmol) of 3,4-dimethoxybenzoyl chloride. The pH of the solution was adjusted to 9.5 with 28.0 ,ul (0.201 mmol) of triethyl~mine and the mixture stirred at 25C for 15 ..~ les. Flash chromatography of the reaction mixture directly on silica gel (40% Et2O in CH2C12) gave the title compound as a white solid (20.0 mg, 24.0% yield) upon trituration with ether.
M.W.: 482.556.
m.p.: 107-18C (shrink).
HPLC: 99.6%.
PMR: Consistent with structure plus ether and water.
M.S.: = M+H = 483 (FAB).
TLC: Rf = 0.26, silica GF (40% Et20 in CH2C12).
CHN: Calc'd as C30H30N2O4-0.15 C4HloO-0.35 H20 (F.W.=500.008):
C, 73.50; H, 6.49; N, 5.60.
Found: C, 73.48; H, 6.31; N, 5.55.
wo 94,07496 ~ 43~ ~ ~ PCI/US93/09152 s ~ J~
60 mg (0.188 mmol) of ~e product of Example 1 was dissolved in 2 ml CH2CL2 and the solution treated wi~ 36.9 mg (0.207 mmol) of nicotinoylchloride hydrochloride. The pH of the mi~ture was adjusted to 9.5 with 58 ~11 (0.416 mmol) of trie~yl amine and the reaction stirred at 25C for 18 hours.
Flash chromatography of ~e reaction mixtllre directly on silica gel (4% MeOH in CH2Cl2) gave the title compound as a white solid (56.8 mg, 71.3% yield) crystallized from ether.
M.W.: 423.494.
m.p.: 205-6C.
HPLC: 99.7 % .
PMR: Consistent with structure.
M.S.: M+H=424 (FAB).
TLC: Rf = 0.26, silica GF (5% MeOH in CH2C12).
2 CHN: Calc'd as C27H25N302:
C, 76.57; H, 5.92; N, 9.92.
Found: C, 76.50; H, 5.90; N, 9.91.
WO 94/07496 21 ~ 31 I 7 PCr/US93tO9152 S ~
60 ml (0.188 mmol) of the product of Example 1 was dissolved in 2 ml CH2Cl2 and the solution treated with 36.9 mg (0.207 mmol) of isonicotinoyl chloride hydrocloride. The pH of the mix~lre was adjusted to 9.5 with 58 ,ul (0.416 mmol) of trie~yl~mine and ~e reaction stirred at 25C for 1 hour.
Flash chromatography of the reaction mixture directly on silica gel (5% MeOH in CH2CL2) gave the title compound as a white solid (56.0 mg, 70.4% yield) crystallized from ether.
M.W.: 423.494.
m.p.: 224-6C.
HPLC: 99.7%
PMR: Consistent with structure.
M.S.: M+H=424 (FAB).
TLC: Rf = 0.23, silica GF (5% MeOH in CH2cl2).
C, 76.57; H, 5.92; N, 9.92.
Found: C, 76.22; H, 5.95, N, 9.74.
WO 94/07496 PCT/US93/0915~
~43~
TABLES
~'' .
In addition to those compounds specifically exemplified above, additional compounds of the present invention are set forth in tabular form 5 below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue experimentation. All variables listed in Table 1 below are with reference to the following generic structure:
~1 o~X,Rl ~ 21 ~ ~ I 1 7 PCI/US93/09152 X
-CH2- ~
o -CH2- H3CCHN~
-CH2- H2N~3 no substituentH3CCHN~3 ~~--NH2 -CH2- ~J
WO 94/07496~,~ 43~ PCl/US93/091 TABLE 1 ~CONTD) X .~ R
-CH2- ~ CH, -CH2- ~--NH CH3 1 s -CH2-HN ~n,CH3 -CH2- ~ , N~o CH3 2s no substituent ~3~' CH3 o ~ NH2 ~ 2I93ll7 WO 94/07496 PCI`/US93/09152 TABLE 1 (CONT'D) X Rl -CH2- ~ ~CH3 o ~N>
-CH2- ~ O
~l~H3C CH3 -CH2- ~NH ~ NH2 no substituent ~NH2 -CH2- ~3`HCCH=CH~ q NH
no substituent ~3--NH CH3 CH W~ NO2 ~43~
TABLE 1 (CONT'D) X ' Rl no substituent ~3~H~H3 ~ o -CH2- H ~N~
H
CH; ~NH2 CH; ~NH CH3 2s -CH2`
-CH2- [~ N ~` H
~ WO 94/07496 21 ~ 31 1 7 PCI/US93/09152 TABLE 1 (CONT'D) X Rl -CH2-~ ~ NN~H
o O CH3 2 o -CH=CH-~1~ NO2 -CH2- H~CN
WO 94/07496 PCI`/US93/Ogl5~
3~
The variables shown in Table 2 are with reference to the following structure:
N
~! 214317 Y Y
OH
/so2~3 /SO2~CI
~SO~ /SO2~F
/S2~ /S2~
OH
~S~ ~SO2~
W094/07496 ~43~'1 PCI/US93/0915~
TABLE 2 (CONT'D) Y Y
Cl NH2 ~SO2~ ` /S02~
O
~ ~S CCHH33 /S2~
HN ~CH3 o H3C ~CH3 ~ NH CH3 /SO2~ `l3`NH2 Z5 ~5O2~D`NH~0 ~CH
WO 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 TABLE 2 (CONT'D) y Y
5~SO2~l3` N' 2 CH3 --~H3CH3 ~Z~ NJ~CH3 ~SO~CH3 ,CH3 ~OZ~o~cH3 S ~ 2 ~SO2~ ~SO2 NH~Z~so2 CH3 ~SO2~,~NH2 WO 94/07496 PCTtUS93/0915~
2i9~3~
TABLE 2 (CONTD) Y y ". CH3 ~SO2 NH~ ~S2~_~o~CH3 1 o--SO2~o~cH3 ~H~
o,~ ,S2 ~H)~
~S2--N~fH3 ~N~NH
WO 94/07496 PCI`/US93/09152 21~3117 The variables shown in Table 3 are with reference to the following structure:
[~CH3 ~N~
J~ Z ~
O H
o~o ~ H
2 o 1 ~,N~N~
2 5 ~ J~H3 H3C ~
Dg~oJ~CH3 H
p'L~3~ 54-o 0 J~ ,~H3CH
0~ ,NH
O
~3 [~ ¢~
WO 94/07496 PCI/US93/09lS2 21~311 7 O Z Z
5 J~ ~
o~N~ SO2 O H
10 ,J~
od` ~N~ N~
N
O H
Il O
2 o S2 N~
OH
o CH3 ~
~--13 2~43~
TABLE 3 (CONT'D) 7 `` 7.
O . O
O~N~0 'J~ J~
H ~[3 od~r SO2~CH3 HN O~,CH3 ~ rCH3 , O CH3 O~CH3 pH HO~
O N O N
~CH3 ~CH3 PCl~/US93/09152 WO 94/07496 2 1 ~ 3 1 1 7 J~l ~I~O~,CH3 o ~, O~N
N
H
~NJ
o~,SO
W O 94/07496PC~r/US93/0915 ~
~43~
RADIOLIGAND BINDING ASSAYS
5The high affinity binding of [3H] Oxytocin (OT)([tyrosyl, 3,5-[3H]oT; 30-60 Ci/mmol; New Fn~l~nd Nuclear. Boston, MA) to uterine OT receptors was based on an assay (Fuchs, A-R; Fuchs, F; Soloff, MS.
1985 J. Clin. Endocrinol. Metab. 60:37) using a crude membrane preparation of uteri taken from diethylstilbestrol dipropionate (DES)-treated (0.3 mg/kg, ip; 18-24) rats. Cornpetition studies were conducted at equilibrium (60 minlltes; 22C) using 1 nM~3H]OT in the following assay rrel. 50 mM Tris-HCl, 5 mM MgC12, and 0.1% BSA, pH 7.4.
Nonspecific binding (10% of the total binding) was determined using 1 ,uM
unlabeled OT and the binding reaction was termin~ted by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, l[nc., Sterling, VA). ICso (the concentration of tested compound that inhibits 50% of OT) was reported, unless otherwise noted.
The measurement of [3H]Vasopressin (AVP) ([phenylalanyl-3,4,5-3H]AVP; 80-90 Ci/mmol, New Fngl~nd Nuclear)binding to a crude membrane preparation of male rat liver (AVP-Vl sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al.
(Butlen, D; Guillon, G; Rajerison, R.M.;Jard, S; Sawyer, W.H.;~I~nning, M. 1978 Mol Ph~ col 14:1006).
Competition assays were conducted at equilibrium (30 minlltes at 30C) using 1 nM [3H]AVP (liver) or 2 nM [3H]AVP (kidney) in the following assay burrel. 100 mM Tris-HCl, S mM MgC12, 0.1% BSA, 50 mM phenylmethylsulfonylfluoride, and 50 mg/ml bacitracin, pH 8Ø
Nonspecific binding (5-10% of the total binding) was determined using 10 ,uM unlabeled AVP, and the binding reaction was termin~ted by filtration as described above for the [3H]oT binding assay.
2l~3ll 7 _ 59 _ ICso values were determined for both [3H]oT and [3H]AVP
binding assays by linear regression of the relation log concentration of compound vs. percent inhibition of specific binding.
Example ICso[3HlOT (nM) 3~700 While the invention has been described and illustrated with 5 reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention.
For example, effective dosages other than the preferred dosages as set forth hereinabove may be applicable as a consequence of variations in ~e 20 responsiveness of the m~mm~l being treated for prevention of prete~n labor, or for other indications for the compounds of the invention indicated above. Likewise, the specific ph~rm~cological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as 25 the type of form~ tion and mode of ~(lmini~tration employed, and such expected variations or differences in the results are collt~nl~lated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
2~4~ Ll~
-Gluceptate Polygalacturonate Gluconate Salicylate Glllt~m~te Stearate Glycollylars~nil~te Sulfate Hexylresorcinate Subac~tate Hydrabamine Succinate Hydrobromide Tannate Hydrochloride Tartrate Hydroxynaphthoate Teoclate Iodide Tosylate Isothionate Triethiodide Lactate Valerate The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, ~nim~l or hllm~n that is being sought by a researcher or clinician.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range.
The term "alkenyl" shall mean straight or branched chain aLkenes with one or more degrees of lm.~ lration at any position on the chain, of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes with one or more degrees of lmc~lllration at any position on ~e chain, of two to ten total carbon atoms, or any number within ~is range.
The term ""aryl" shall mean phenyl, naphthyl or fluorenyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms.
Whenever the terrns "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy) they shall be inte~ ed as including those limitations given above for "alkyl" and ~ WO94/07496 21~3117 PCl/US93/09152 "aryl". Designated numbers of carbon atoms (e.g. C1 1o) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "oxo" shall refer to the substituent =0.
The term "azimidobenzene" (also known as benzotriazole) shall refer to the moiety 1 o N~ ~
The term "spirocyclic indenyl" shall refer to the moiety 1~1 The term "halogen" shall include iodine, br~ e, chlorine and fluorine.
The term "preterm labor" shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or ~ e of the membranes.
The term "dysmenorrhea" shall mean painful menstruation.
The term "Caesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.
WO94/07496~ 21~311'Z PCl/US93/09152~
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
The ability of the compounds o~ ~ormula I to antagonize 5 oxytocin makes these compounds useful as ph~ cologic agents for m~mm~l~, especially for hllm~n~, for the treatment and prevention of disorders wherein oxytocin may be involved. F.x~mples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean 1 delivery-Because of the known relationship of vasopressin to oxytocin,the compounds of the present invention are also useful as vasopressin antagonists. Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their 15 use as diuretics and their use in congestive heart failure.
The compounds of the present invention can be ~lmini~tered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and em~ ions. Likewise, they may also be 20 ?~flmini~tered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the ph~ ceutical arts. An effect*e but non-toxic amount of the compound desired can be employed as a tocolytic agent.
The dosage regimen l~tili7in~ the compounds of the present 25 invention is selected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of ~(lmini~tration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily 30 determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
2I~311 7 WO 94/07496 - PCr/US93/09152 Oral dosages of the present invention, when used for the indicated effects, will range between about 0.3-6.0 gm/day orally.
Intravenously, the most preferred doses will range from 0.1 to about 10 mg/mimlt~ during a constant rate infusion. Advantageously, compounds of 5 the present invention may be ~lministered in a single daily dose, or the total daily dosage may be ~(lmini~tered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be ~1mini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
To be ~lmini~tered in the form of a transdermal delivery system, the dosage a~mini~tration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein 15 described in detail can form the active ingredient, and are typically ~lmini~tered in ~ ix~ e with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of ~lmini~tration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with 20 conventional ph~ ceutical practices.
For instance, for oral ~lmini~tration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic ph~m~ceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, 25 lubricants, disintegrating agents and coloring agents can also be incorporated into the mix~lre. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tr~g~r~ntl or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
3 Lubricants used in these dosage forms include sodium oleate, sodium stearate, m~gnesium stearate, sodium benzoate, sodium acetate, sodium wo 94,07496 2 1 ~3 11~ PCI/US93/09152~
chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, 7~nth~n gum and the like.
The compounds of the present invention can also be ~lmini~tered in the form of liposome delivery systems, such as small 5 lmil~mellar vesicles, large lmil~mellar vesicles and mllltil~mellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearyl~mine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the o compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with 15 palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic 20 block copolymers of hydrogels.
The compounds of formula I can be prepared readily according to ~e following reaction Schemes (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis 25 procedures. ~ these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, 3 however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples fur~er illustrate details for ~ WO 94/07496 2 1 ~ 3 1 1 7 PCr/US93/0915' the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless 5 noted other~,vise.
WO 94/07496 PCI/US93/09~52 ~
2~3l~l Cl-CO CH2~R
N EDC/HBT/DMF or BOP
R~
/ ~+~X-CO-CI ~X
~ R3/`3~ j2N~o-co~
N ~ /~(H)n N (WhereX=N,OorS) X = O, N, S, CH2 o~O
n=1,2 ~ wo 94/07496 2 1 ~ 3 1 1 7 PCl /US93/09152 SCHFMF ?
N Hydro9enation N
O~CH2 ~O~cH2 ¢~ ~
N2 / ~ NH2 [OH--]/
~ / BOP / \ BOP
20 ~C~ ~ ~
+ HOOCcH2~ NH2 NHCOR
H
WO 94/07496 PCI`/US93/0915'' 2~43~
SCHEM~ 3 CH Where W is a ~ 3 ~W~W~ suitable leaving group NH2 N and Z is a protecting z group such as BOC or CBZ
[~ N~l Deprotection [~CH3 ~/ N~z / ~R/ N~H
3// R~
/ Cl-CO~/,~
~CI 13 / R' R O~ ~N~
~ WO 94/07496 2 1 4 3 1 1 7 PCI~/US93/09152 SCHFME 4 ~=~/R
Cl-CO-CH2~
s ~CH3 or HOOCCH2~R
EDC/HBT/DMF or BOP
~ Cl CO~,~ ¢N~CH3 l 5 I~CH3 X-CO-CI~ o X
~ ~ H
Z H3CJ~ ~/)n R3 ~ ~ (Where X= N,O or S) X=O,N,S,CH2 n=1,2 ~
WO 94/07496 PCl/lJS93/09152~
2~3il~
Abbreviations used in the Examples are as follows:
EDC = l-ethyl-3-(3-dimethylaminQpropyl)carbodiimide hydrochloride .
BOC = tert-butoxycarbonyl TEA = triethyl~mine DIEA = diisopropylethyl~mine BOP = benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate THF = tetrahydrofuran DMF = dimethylformamide LAH = lithium all-minllm hydride TFA = trifluoroacetic acid HPLC Method A = 15 min. linear gradient 95:5 A:B to 0:100 A:B
A - H20 cont~inin~ 0.1% by vol. TFA
B = CH3CN cont~inin~ 0.1% by vol. TFA
2.0 mL/min flow rate 12 cm Clg reverse phase column W detection (215 nm) TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.
~ wo 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 s 0~
0~
70 mg (0.316 mmol) of spiro(lH-indene-1,4'-piperidine HC1) was dissolved in 3 ml DMF and the solution treated with 52.5 mg (0.347 mmol) of 4-aminophenyl acetic acid followed by 161 mg (0.363 mmol) of benzotriazol-1-yl-oxy(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 142 ~11 15 (0 794 mmol) of diisopropylethyl~mine and the mixture stirred at 25 for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2S04, filtered 20 and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (1:1 of ethyl acetate: CH2Cl2) gave the title compound as a white foam (41 mg, 40.6% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: 318.402.
m.p.: 60-87C (sinter) HPLC: 96.3%
PMR: Consistent with structure plus ether and water M.S.: M+H = 319 (FAB).
- TLC: Rf = 0.34, Silica GF (1:1 of EtOAc: CH2Cl2).
CHN: Calc'd as C21H22N2O-0.05 C4H100-0.30 H20 (F.W. = 327.532):
W O 94/07496 43~ PC~r/US93/09152 C, 77.74; H, 7.11; N, 8.55.
Found: C, 77.83; H, 6.80; N, 8.23.
.~ , .
~ ¢~NH CH3 l.lgm (3.45 mmol) of the product of Fx~mrle 1 was dissolved in 15 ml of CH2C12 and ~e solution treated with 0.27 ml (3.80 rnrnol) of acetyl chloride. The pH was adjusted to 9.5 with 0.55 ml (3.82 mmol) of triethyl~mine and the mixture stirred at 25C for 1 hour.
Flash chromatography of ~e reaction mixture directly on silica gel (3:1 of ethyl acetate: CH2C12) gave the title compound as a crystalline solid (992 mg, 79.3% yield) from ethyl acetate.
M.W. 360.438.
m.p.: 217-9C.
HPLC: 99.5%
PMR: Consistent with structure.
M.S.: M+H=361(PAB).
TLC: Rf = 0.31, Silica GF (3:1 of ethyl acetate: CH2C12).
CHN: Calc'd as C23H24N202:
C, 76.64; H, 6.71; N, 7.77.
Found: C, 76.26; H, 6.80; N, 7.76.
WO 94/07496 - PClr/US93/09152 0~
125 mg (0.564 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF and the solution treated with 112 mg (0.620 mmol) of o-nitrophenyl acetic acid followed by 286 mg (0.649 mmol) of benzotriazol-l-yl-oxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent). The pH of the solution was adjusted to 9.5 with 307 ,ul (1.75 mmol) of diisopropyl ethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with H20 and extracted with ethyl acetate (3x). The organic extracts were 20 combined, washed wi~ water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dIyness in vacuo. Flash chromatography of the crude product on silica gel (3% Et2O in CH2Cl2) gave 155.7 mg (79.4% yield) of the title compound as a white foam after evaporation in vacuo.
M.W.: 348.386.
m.p.: 60-75C (sinter).
HPLC: 93.4%.
PMR: Consistent with structure plus water.
M.S.: M+H = 349.2 (FAB).
TLC: Rf = 0.29, Silica GF (4% Et2O in CH2C12).
CHN: Calc'd as C21H20N2O3-0.30 H20 (~.W. = 353.8):
C, 71.28; H, 5.87; N, 7.92.
WO 94/07496 21 ~3 11~ PCI/US93/09152~
Found: C, 71.35; H, 5.64; N, 7.91.
FXAMPLE~
., H o ' 0~~
250 mg (1.13 mmol) spiro(lH-indene-1,4'-piperidine) hydro-chloride was dissolved in 10 ml DMF and the solution treated with 15 350 mg (1.24 mmol) of 2-(t-butyloxyaminomethyl)-phenylacetic acid followed by 575 mg (1.30 mmol) of benzotriazol-l-yloxytris (dimethyl-amino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (13% Et2O in CH2C12) gave the title compound 25 isolated as a crystalline solid (285 mg, 56% yield) from diethyl ether.
M.V.: 448.542.
m.p.: 165-7C.
HPLC: 97.2%.
30 PMR: Consistent wi~ structure plus ether.
M.S.: M+H + Thioglycerol (M.W. = 108) = 5573 (FAB).
TLC: Rf = 0.48, Silica GF (20% ET2O in CH2C12)-~WO 94/07496 2 1 ~ 3 1 1 7 PCI`/US93/09152 CHN: Calc'd as C27H32N204-0.10 C4HloO (F.W. = 455.954) C, 72.17; H, 7.30; N, 6.14.
Found: C, 72.12; H,7.33; N, 6.29.
s EXAMPLE S
~ 1 ~N
O ~ N O
H
250 mg (1.13 mmol) of spiro(lH-indene-1,4'-piperidene) hydrochloride was dissolved in 10 ml DMF and the solution treated with 350 mg (1.24 mmol) of 3-(t-butyloxyaminomethyl)-phenyl acetic acid followed by 575 mg (1.30 mmol) of benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorophosphate (BOP Reagent). The pH of the 20 solution was adjusted to 9.5 with 550 ,ul (3.14 mmol) of diisopropyl-ethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washedl with water (lx), dried over Na2S04, filtered, and 25 stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (20% Et2O in CH2Cl2) gave the title compound as a white foam (328 mg, 65.0% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: 448.542.
30 m.p.: SS-72C (sinter).
HPLC: 99.6%
PMR: Consistent with structure plus water.
W094/07496 2~43l~rt PCI/US93/09152 M.S.: M+H + Thioglycerol (M.W. - 108) = 557.6 (FAB).
TLC: Rf = 0.52, Silica GF (25% Et2O in Ch2cl2).
CHN: Calc'd as C27H32N2O4-0 15 H20 (F.W. = 451.269):
C, 71.86; H, 7.21; `-N, 6.21.
Found: C, 71.83; H, 7.09; N, 6.45.
l o ~>~ ,~¢N>
70 mg (0.220 mmol) of the product of Fx~mple 1 was dissolved in 5 ml DMF and the solution treated with 39.3 mg (0.242 mmol) of imidazole-4-acetic acid-hydrocloride followed by 32.7 mg (0.242 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 46.4 mg (0.242 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC). The pH was adjusted to 9.5 with triethyl~mine and the mixture stirred at 25C
or 4 hours.
DMF was removed in vacuo and the crude residue treated with water and extracted with e~yl acetate (3x). The organic extracts were combined, washed with water (1x), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2C12:MeOH: Conc NH40H) gave the title compound as a white solid (50.8 mg, 54.2% yield) after evaporation in vacuo and trituration with ether.
M.W.: 426.50.
m.p.: 104-36C (sinter).
21~3117 HPLC: 99.3%
PMR: Consistent with structure plus ether, CH2C12, and water.
M.S.: M+H + 427.1 (FAB).
TLC: Rf = 0.32, Silica GF (80:10:1 of CH2Cl2: MeOH:
Conc. NH40H).
CHN: Calc'd a C26H26N4)2-0.10 CH2C12-0.10:
C4H1oO-0.50 H20 (F.W. = 451.212):
C, 70.53; H, 6.26; N, 12.42.
Found: C, 70.56; H, 6.04; N, 12.64.
~ NH2 85 mg (0.267 mmol) of the product of Example 1 was dissolved in S ml DMF and the solution treated with 72.3 mg (0.294 mmol) of N-t-butyloxycarbonyl-L-glllt~mine followed by 39.7 mg (0.294 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 56.3 mg (0.294 mmol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The 25 pH was adjusted to 9.5 with 55 ,ul (0.395 mmol) of triethyl~mine (Et3N) and the ~ Ul~ stirred at 25C for 1.5 hours.
A second portion of 72.3 mg (0.294 mmol) of N-t-butyloxy-carbonyl-L-~ t~mine, 39.7 mg (0.294 mmol) of H B T, 56.3 mg (0.294 mmol) of EDC and 55 ,ul (0.395 mmol) of Et3N was added and the 30 mixture stirred at 25C for 18 hours.
DMF was removed in vacuo and the residue treated with H20 and extracted with ethyl acetate (3x). The organic extracts were com-WO 94/07496~ 3~ PCr/US93/0915 bined, washed with water (lx), brine (lx), dried over Na2S04, filtered and stripped to dryness in vacuo. Flash chromatography of ~e crude product on silica gel (6% MeOH in CH2C12) ga~ the title compound as a white solid (57.4 mg, 39.3% yiel~d) after evaporation in vacuo and 5 trituration with ether.
M.W.: 546.646.
m.p.: 104-47C (sinter).
HPLC: 99.1 %.
PMR: Consistent with structure plus water and ether.
M.S.: M+H = 547 (FAB).
TLC: Rf = 0.18, Silica GF (4% MeOH in CH2C12).
CHN: Calc'd as C31H3gN4O5-0.10 C4HloO-0.75 H20 (F.W. = 5657.597):
C, 66.44; H, 7.19; N, 9.87.
Found: C, 66.42; H, 6.98; N, 10.04.
N ~Br O~J
75 mg (0.338 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF and the solution treated with 80.0 mg (0.372 mmol) of 4-bromophenyl acetic acid followed by 171.9 mg 30 (0.389 mmol) of benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP Reagent). The pH of ~e solution was adjusted ~ WO94/07496 21~3117 PCI/US93/09152 to 9.5 with 125 ml (0.710 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were 5 combined, washed with water (lx), brine (lx), dried over Na2SO4, ~1ltered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (5% Et20 in CH2Cl2) gave the title compound as a white foam (30 mg, 23.3% yield) upon coevaporation with ether (3x) in vacuo.
M.W.: = 382.282.
m.p.: 44-58C (sinter).
HPLC: 99.5%.
PMR: Consistent with structure plus water.
M.S.: M+H = 382.1/384.1 at 1/1 (FAB).
TLC: Rf = 0.44, Silica GF (6% Et2O in ch2c12)-CHN: Calc'd as C21H20BrNo-o.4o H2O (F.W. = 389.513):
C, 64.75; H, 5.38; N, 3.60.
Found: C, 64.51; H, 5.06; N, 3.60.
~NH~ >
375 mg (1.18 mmol) of the product of Example 1 was dissolved in 10 ml DMF and the solution treated with 179 mg (1.30 mmol) of urocanic acid followed by 175 ml (1.29 mmol of 1-hydroxybenzo-wo 94/07496 ~ ~3~ ~'1 PCI`/US93/0915 triazole hydrate (HBT) and 248.5 mg (1.30 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC). The pH of the solution was adjusted to 9.5 with 414 ,ul (0.298 mmol) of triethyl~mine (Et3N) and the reaction stirred at 25C for~6~hours.
A second portion consisting of 179 mg (1.30 rnmol) of urocanic acid, 175 mg (1.29 mmol) of HBT, 249 (1.30 mmol) of EDC and 414 ~11 (0.298 mmol) of Et3N was added and the reaction stirred at 25C
for 18 hours.
DMP was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (1x), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2Cl2: MeOH: Conc. NH40H) gave the title compound as a crystalline solid (106 mg, 20.5% yield) from ethyl acetate.
M.W.: = 438.51.
m.p.: 170-85C (Physical Change); 228-30C (melt).
HPLC: 99.0%.
PMR: Consistent with structure plus water.
2 0 M.S.: M+H = 439 (FAB).
TLC: Rf = 0.36, silica GF (80:10:1 of CH2Cl2:
MeOH: Conc. NH40H).
CHN: Calc'd as C27H26N402-0.95 H20 (F.W.455.468):
C, 71.17; H, 6.17; N, 12.30.
25 Found: C, 71.05; H, 5.78; N, 11.91.
WO 94/07496 PCl /US93/09152 ., . 0~0>
60 mg (0.271 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 4 ml DMF and the solution treated with 53.7 mg (0.298 mmol) of 3,4-methylenedioxy phenyl acetic acid followed by 137.8 mg (0.312 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 wi~ 100,ul (0.569 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hour.
DMF was removed in vacuo and the crude residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed wi~ water (lx), brine (lx), dried over Na2SO4, fîltered 20 and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (6% Et2O in CH2Cl2) gave the title compound as a c~ystalline solid (32.4 mg, 34.3% yield) from ether.
M.W.: 347.396.
m.p.: 123-5C.
HPLC: 99.4%
PMR: Consistent with structure plus water.
M.S.: M+H = 348.1 (FAB).
TLC: Rf = 0.30, Silica GF (6% Et2O in Ch2cl2) - CHN: Calc'd as C22H21NO3-0.15 H2O (F.W. = 350.119):
C, 75.47; H, 6.13; N, 4.00.
Found: C, 75.51; H, 5.79; N, 4.01.
WO 94/07496 PCr/US93/0915~
3~
EXAMPLE 11 ~;
N
300 mg (1.35 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 10 ml DMF and the solution treated with 341 mg (1.49 mmol) of p-bromoethyl phenyl acetic acid followed by 687 15 mg (1.55 mmol) of benzotriazol-l-yloxy(dimethylamino) phosphonium hexafluorophosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 769 ~11 (4.39 mml) of diisopropylethyl~mine and the mixtllre stirred at 25C for 18 hours.
DMF was removed in vacuo and the crude residue treated with 20 water and extracted with ethyl acetate (3x). The oganic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (12% Et2O in CH2Cl2) gave the title compound as a white foam (318 mg, 59.3% yield) upon coevaporation with 25 ether (3x) in vacuo.
M.W.: 450.52.
m.p.: 50-64C.
HPLC: 94.9%.
PMR: Consistent with structure plus water.
M.S.: M+H = 451 (FAB).
TLC: Rf = 0.27, silica GF (15% Et2O in CH2C12)-.
WO 94/07496 2 1 ~ 3 1 ~ 7 PCI/US93/09152 CHN: Calc'd as C28H26N402-1.30 H20 (F.W. = 473.965):
C, 70.95; H, 6.08; N, 11.82.
Found: C,70.98; H, 5.81; N, 12.00.
~ N~N>
60 mg (0.188 mmol) of the product of Example 1 was 15 dissolved in 3 ml DMF and the solution treated with 36.6 mg (0.226 mmol) of benzoimidazole-5-carboxylic acid followed by 30.5 mg (0.226 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 43.3 mg (0.226 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH was adjusted to 9.5 with 63.0 ~1 (0.453 mmol) of triethyl~mine and the 20 mixture stirred at 25C for 20 hours.
A second portion consisting of 18.3 mg (0.226 mmol) of benzoimidazole-5-carboxylic acid, 15.3 mg (0.113 mmol) HBT, 21.7 mg (0.113 mmol) EDC and 31.5 ~11 (0.227 mmol) of triethyl~mine was added and the reaction stirred at 25C for 6 hours.
DMF was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (100:10:1 of CH2Cl2:MeOH:Conc. NH40H) gave the title compound as a crystalline solid (51.5 mg, 59.1% yield) from ethyl acetate.
W094/07496 ~ PCr/lJS93/0915 M.W.: 462.53.
m.p.: 212-6C.
HPLC: 98.8%. ~ .
PMR: Consistent with structure.
M.S.: M+H=463 (FAB).
TLC: Rf = 0.34, silica GF (80:10:1 of C12:MeOH:Conc NH4OH).
CHN: Calc'd as C29H26N402: (m.w. - 462.53):
C, 75.30; H, 5.67; N, 12.11.
Found: C, 75.18; H, 5.66; N, 12.06.
~ I
O~N CH3 ~f CH3 O
100 mg (0.451 mmol) of spiro(lH-indene-1,4'-piperidine) hydrochloride was dissolved in 3 ml DMF N-ethoxycarbonyl-a-(4-Acet~miclophenyl)-glycine followed by 229 mg (0.519 mrnol) of 2 5 benzotriazol- 1 -yl-oxytris(dimethylamino)phosphonium hexafluoro-phosphate (BOP Reagent). The pH of the solution was adjusted to 9.5 with 166 ~11 (0.947 mmol) of diisopropylethyl~mine and the mixture stirred at 25C for 1 hours.
DMF was removed in vacuo and the crude residue treated with 30 water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude WO 94/07496 - PCTtUS93/091~2 product on silica gel (3% MeOH in CH2Cl2) gave the title compound isolated as a crystalline solid (139 mg, 68.8% yield) from ether.
M.W.: 447.516.
m.p.: 216-8C.
HPLC: 98.1 %.
PMR: Consistent with structure.
M.S.: M+H=448.1 (FAB).
TLC: Rf = 0.27, silica GF (4% MeOH in CH2Cl2).
CHN: Calc'd as C26H29N304 (F.W. - 447.516):
C, 69.78; H, 6.53; N, 9.39.
Found: C, 69.67; H, 6.51; N, 9.55.
~ H
74.4 mg (0.170 mmol) of the product of Example 9 was dissolved in 10 ml of absolute ethanol, treated with 15 mg 10% Pd on C
25 under a nitrogen atmosphere, and hydrogenated at 60 psi for 3 hours. The mixhlre was filtered through SoLka Floc~ to remove catalyst and the filter pad was washed thoroughly with fresh absolute ethanol. The filtrate was evaporated to dryness in vacuo and the residue was flash chromatographed on silica gel (60:10:1 of CH2Cl2:MeOH:H2O:HoAc). The product 30 fractions were combined, stripped to dryness in vacuo, and the residue treated with dilute NaHCO3(aq) and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (1x), dried over WO 94/07496 PCl /US93/09~5~
~43~
Na2SO4, filtered and stripped to dryness in vacuo. The residue was coevaporated with ether (3x), then tri~rated with ether and filtered to give the title compound as a white solid (44.8 mg, 59.7% yield).
M.W.: 442.542.
m.p.: 89-128C.
HPLC: 99.6%.
PMR: Consistent wi~ structure plus e~er, ethyl acetate and water.
M.S.: M+H=443.1 (FAB).
o TLC: Rf = 0.29, silica GF (60:10:1:1 of CH2Cl2:MeOH:H2O:HoAc).
CHN: Calc'd as C27H30N4O2-0.15 C4HloO-O.10 C4HgO2-0.35 H20:
C, 71.74; H,7.10; N, 11.95.
Found: C, 71.68; H,7.05; N, 11.75.
~3~ N~
2s 50 mg (0.157 mmol) of the product of F~mple 1 was dissolved in 2 ml DMF and the solution treated with 27.8 mg (0.173 mmol) of indole-5-carboxylic acid followed by 23.3 mg (0.173 mmol of l-hydroxybenzotriazole hydrate (HBT) and 33.1 mg (0.173 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC).
The pH of the solution was adjusted to 9.5 with 49 ~1 (0.350 mmol) of triethyl~mine and the reaction stirred at 25C for 1 hour.
WO 94/07496 2 1 4 3 1 1 7 PCr/US93/09152 A second portion consisting of 13.0 mg (0.081 mmol) of indole-5-carboxylic acid, 12.0 mg (0.089 mmol) HBT, 15.0 mg (0.078 mmol) EDC, and 22.1 lul (0.159 mmol) of triethyl~min~ was added and ~e reaction stirred at 25C for 1 hour. DMF was removed in vacuo and the 5 residue treated with water and extracted with ethyl acetate (3x). The organic layers were combined, washed with water (lx), brine (1x), dried over Na2SO4, filtered and stripped to dryness in vacuo. Flash chromatography of the crude product on silica gel (230:10:1 of CH2Cl2:MeOH:Conc. NH40H) gave the title compound as an off-white solid (30.0 mg, 37.6% yield) upon trituration with ethyl acetate.
M.W.: 461.54.
m.p.: 241-3C.
HPLC: 97.7%.
PMR: Consistent with structure plus water.
M.S.: M+H=462 (FAB).
TLC: Rf = 0.25, silica GF (200:10:1 of CH2Cl2:MeOH:conc.
NH4OH) CHN: Calc'd as C30H27N302-0.75 H2O. (F.W.=492.701):
C, 75.08; H, 6.16; N, 8.53.
Found: C, 74.97; H,. 5.80; N, 8.47.
~XAMPLE 16 ~ O
~HN ~cN N
~43~
55 mg (0.173 mmol) of the product of Example 1 was dissolved in 2 ml DMF and the solution was treated with 33.9 mg (0.208 mmol) of benzotriazole-5-carboxylic ac~d~followed by 28.1 mg (0.208 mmol) of l-hydroxybenzotriazole hydrate (HBT) and 39.9 mg (0.208 s mmol of l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). The pH of the solution was adjusted to 9.5 with 66.6 ~1 (0.478 mmol) of triethylamine and the reaction stirred at 25C for 18 hours.
DMF was removed in vacuo and the residue treated with water and extracted with ethyl acetate (3x). The organic extracts were combined, washed with water (lx), brine (lx), dried over Na2SO4, filtered and stripped in dryness in vacuo. Flash chromatography of the crude product on silica gel (88:10:1 of CH2C12:MeOH: Conc. NH40H) gave the title compound as a crystalline solid (39.8 mg, 49.8% yield from ethyl acetate.
M.W.: 463.52.
m.p.: 229-32C.
HPLC: 99.6%
PMR: Consistent with structure plus ethyl acetate.
M.S.: M+H=464 (FAB).
TLC: Rf = 0.33, silica GF (80:10:1 of CH2C12:MeOH:Conc.
NH40H) CHN: Calc'd as C2gH25N5O2-0.05 C4H802 (F.W. = 467.948):
C, 72.38; H, 5.47; N, 14.97.
Found: C, 72.39; H, 5.33; N, 14.92.
~ WO 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 ~ ~ ~[OCH
55.0 mg (0.173 mmol) of the product of F.x~mrle 1 was dissolved in 3 ml CH2C12 and the solution treated with 37.9 mg (0.189 mmol) of 3,4-dimethoxybenzoyl chloride. The pH of the solution was adjusted to 9.5 with 28.0 ,ul (0.201 mmol) of triethyl~mine and the mixture stirred at 25C for 15 ..~ les. Flash chromatography of the reaction mixture directly on silica gel (40% Et2O in CH2C12) gave the title compound as a white solid (20.0 mg, 24.0% yield) upon trituration with ether.
M.W.: 482.556.
m.p.: 107-18C (shrink).
HPLC: 99.6%.
PMR: Consistent with structure plus ether and water.
M.S.: = M+H = 483 (FAB).
TLC: Rf = 0.26, silica GF (40% Et20 in CH2C12).
CHN: Calc'd as C30H30N2O4-0.15 C4HloO-0.35 H20 (F.W.=500.008):
C, 73.50; H, 6.49; N, 5.60.
Found: C, 73.48; H, 6.31; N, 5.55.
wo 94,07496 ~ 43~ ~ ~ PCI/US93/09152 s ~ J~
60 mg (0.188 mmol) of ~e product of Example 1 was dissolved in 2 ml CH2CL2 and the solution treated wi~ 36.9 mg (0.207 mmol) of nicotinoylchloride hydrochloride. The pH of the mi~ture was adjusted to 9.5 with 58 ~11 (0.416 mmol) of trie~yl amine and the reaction stirred at 25C for 18 hours.
Flash chromatography of ~e reaction mixtllre directly on silica gel (4% MeOH in CH2Cl2) gave the title compound as a white solid (56.8 mg, 71.3% yield) crystallized from ether.
M.W.: 423.494.
m.p.: 205-6C.
HPLC: 99.7 % .
PMR: Consistent with structure.
M.S.: M+H=424 (FAB).
TLC: Rf = 0.26, silica GF (5% MeOH in CH2C12).
2 CHN: Calc'd as C27H25N302:
C, 76.57; H, 5.92; N, 9.92.
Found: C, 76.50; H, 5.90; N, 9.91.
WO 94/07496 21 ~ 31 I 7 PCr/US93tO9152 S ~
60 ml (0.188 mmol) of the product of Example 1 was dissolved in 2 ml CH2Cl2 and the solution treated with 36.9 mg (0.207 mmol) of isonicotinoyl chloride hydrocloride. The pH of the mix~lre was adjusted to 9.5 with 58 ,ul (0.416 mmol) of trie~yl~mine and ~e reaction stirred at 25C for 1 hour.
Flash chromatography of the reaction mixture directly on silica gel (5% MeOH in CH2CL2) gave the title compound as a white solid (56.0 mg, 70.4% yield) crystallized from ether.
M.W.: 423.494.
m.p.: 224-6C.
HPLC: 99.7%
PMR: Consistent with structure.
M.S.: M+H=424 (FAB).
TLC: Rf = 0.23, silica GF (5% MeOH in CH2cl2).
C, 76.57; H, 5.92; N, 9.92.
Found: C, 76.22; H, 5.95, N, 9.74.
WO 94/07496 PCT/US93/0915~
~43~
TABLES
~'' .
In addition to those compounds specifically exemplified above, additional compounds of the present invention are set forth in tabular form 5 below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue experimentation. All variables listed in Table 1 below are with reference to the following generic structure:
~1 o~X,Rl ~ 21 ~ ~ I 1 7 PCI/US93/09152 X
-CH2- ~
o -CH2- H3CCHN~
-CH2- H2N~3 no substituentH3CCHN~3 ~~--NH2 -CH2- ~J
WO 94/07496~,~ 43~ PCl/US93/091 TABLE 1 ~CONTD) X .~ R
-CH2- ~ CH, -CH2- ~--NH CH3 1 s -CH2-HN ~n,CH3 -CH2- ~ , N~o CH3 2s no substituent ~3~' CH3 o ~ NH2 ~ 2I93ll7 WO 94/07496 PCI`/US93/09152 TABLE 1 (CONT'D) X Rl -CH2- ~ ~CH3 o ~N>
-CH2- ~ O
~l~H3C CH3 -CH2- ~NH ~ NH2 no substituent ~NH2 -CH2- ~3`HCCH=CH~ q NH
no substituent ~3--NH CH3 CH W~ NO2 ~43~
TABLE 1 (CONT'D) X ' Rl no substituent ~3~H~H3 ~ o -CH2- H ~N~
H
CH; ~NH2 CH; ~NH CH3 2s -CH2`
-CH2- [~ N ~` H
~ WO 94/07496 21 ~ 31 1 7 PCI/US93/09152 TABLE 1 (CONT'D) X Rl -CH2-~ ~ NN~H
o O CH3 2 o -CH=CH-~1~ NO2 -CH2- H~CN
WO 94/07496 PCI`/US93/Ogl5~
3~
The variables shown in Table 2 are with reference to the following structure:
N
~! 214317 Y Y
OH
/so2~3 /SO2~CI
~SO~ /SO2~F
/S2~ /S2~
OH
~S~ ~SO2~
W094/07496 ~43~'1 PCI/US93/0915~
TABLE 2 (CONT'D) Y Y
Cl NH2 ~SO2~ ` /S02~
O
~ ~S CCHH33 /S2~
HN ~CH3 o H3C ~CH3 ~ NH CH3 /SO2~ `l3`NH2 Z5 ~5O2~D`NH~0 ~CH
WO 94/07496 2 1 ~ 3 1 1 7 PCI /US93/09152 TABLE 2 (CONT'D) y Y
5~SO2~l3` N' 2 CH3 --~H3CH3 ~Z~ NJ~CH3 ~SO~CH3 ,CH3 ~OZ~o~cH3 S ~ 2 ~SO2~ ~SO2 NH~Z~so2 CH3 ~SO2~,~NH2 WO 94/07496 PCTtUS93/0915~
2i9~3~
TABLE 2 (CONTD) Y y ". CH3 ~SO2 NH~ ~S2~_~o~CH3 1 o--SO2~o~cH3 ~H~
o,~ ,S2 ~H)~
~S2--N~fH3 ~N~NH
WO 94/07496 PCI`/US93/09152 21~3117 The variables shown in Table 3 are with reference to the following structure:
[~CH3 ~N~
J~ Z ~
O H
o~o ~ H
2 o 1 ~,N~N~
2 5 ~ J~H3 H3C ~
Dg~oJ~CH3 H
p'L~3~ 54-o 0 J~ ,~H3CH
0~ ,NH
O
~3 [~ ¢~
WO 94/07496 PCI/US93/09lS2 21~311 7 O Z Z
5 J~ ~
o~N~ SO2 O H
10 ,J~
od` ~N~ N~
N
O H
Il O
2 o S2 N~
OH
o CH3 ~
~--13 2~43~
TABLE 3 (CONT'D) 7 `` 7.
O . O
O~N~0 'J~ J~
H ~[3 od~r SO2~CH3 HN O~,CH3 ~ rCH3 , O CH3 O~CH3 pH HO~
O N O N
~CH3 ~CH3 PCl~/US93/09152 WO 94/07496 2 1 ~ 3 1 1 7 J~l ~I~O~,CH3 o ~, O~N
N
H
~NJ
o~,SO
W O 94/07496PC~r/US93/0915 ~
~43~
RADIOLIGAND BINDING ASSAYS
5The high affinity binding of [3H] Oxytocin (OT)([tyrosyl, 3,5-[3H]oT; 30-60 Ci/mmol; New Fn~l~nd Nuclear. Boston, MA) to uterine OT receptors was based on an assay (Fuchs, A-R; Fuchs, F; Soloff, MS.
1985 J. Clin. Endocrinol. Metab. 60:37) using a crude membrane preparation of uteri taken from diethylstilbestrol dipropionate (DES)-treated (0.3 mg/kg, ip; 18-24) rats. Cornpetition studies were conducted at equilibrium (60 minlltes; 22C) using 1 nM~3H]OT in the following assay rrel. 50 mM Tris-HCl, 5 mM MgC12, and 0.1% BSA, pH 7.4.
Nonspecific binding (10% of the total binding) was determined using 1 ,uM
unlabeled OT and the binding reaction was termin~ted by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, l[nc., Sterling, VA). ICso (the concentration of tested compound that inhibits 50% of OT) was reported, unless otherwise noted.
The measurement of [3H]Vasopressin (AVP) ([phenylalanyl-3,4,5-3H]AVP; 80-90 Ci/mmol, New Fngl~nd Nuclear)binding to a crude membrane preparation of male rat liver (AVP-Vl sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al.
(Butlen, D; Guillon, G; Rajerison, R.M.;Jard, S; Sawyer, W.H.;~I~nning, M. 1978 Mol Ph~ col 14:1006).
Competition assays were conducted at equilibrium (30 minlltes at 30C) using 1 nM [3H]AVP (liver) or 2 nM [3H]AVP (kidney) in the following assay burrel. 100 mM Tris-HCl, S mM MgC12, 0.1% BSA, 50 mM phenylmethylsulfonylfluoride, and 50 mg/ml bacitracin, pH 8Ø
Nonspecific binding (5-10% of the total binding) was determined using 10 ,uM unlabeled AVP, and the binding reaction was termin~ted by filtration as described above for the [3H]oT binding assay.
2l~3ll 7 _ 59 _ ICso values were determined for both [3H]oT and [3H]AVP
binding assays by linear regression of the relation log concentration of compound vs. percent inhibition of specific binding.
Example ICso[3HlOT (nM) 3~700 While the invention has been described and illustrated with 5 reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention.
For example, effective dosages other than the preferred dosages as set forth hereinabove may be applicable as a consequence of variations in ~e 20 responsiveness of the m~mm~l being treated for prevention of prete~n labor, or for other indications for the compounds of the invention indicated above. Likewise, the specific ph~rm~cological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as 25 the type of form~ tion and mode of ~(lmini~tration employed, and such expected variations or differences in the results are collt~nl~lated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims (13)
1. A compound or the pharmaceutically acceptable salts and esters thereof, of the formula X-Y-Z-R1, wherein X is or W is hydrogen or acetate;
Y is -CO- or -SO2-;
Z is an optional substituent that, when present, is one or more of N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m-CHR-, -(CH2)m- or -CHCHOH-;
R is hydrogen, C1-5 alkyl or C1-5 alkoxycarbonylamino, quinuclidinylaminocarbonylamino;
R1 is-CH3,-CH(CH3)2, , , , , , , , , , , , , , -NR4R5 or-NCOR6;
R2 is hydrogen, hydroxy, carboxyl, acetyl, cis or trans oximino, nitro,spirocyclic indenyl, N-spiroindanepiperidinyl, O-Het where Het is imidazole or benzimidazole or azimidobenzene, or where R2 is further defined as -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7, -(CH2)m-NR8R9, -(CH2)m-NHCO-(CH2)mR7, -(CH2)m-NHCO-CHR7R7, -(CH2)m-NHCO-CH=CHR7, -(CH2)m-CO-O-R7, -(CH2)m-CO-O-(cH2)mR7, -(CH2)m-CO-O-CHR7R7, -(CH)m-CO-O-CH=CHR7, -NHSO2R-where R is as defined above, NHSO2R7, -(CH2)m-O-R10, -SO2R10, -COR11, , , , or or one to two substituents selected from the group consisting of or ;
R3 is one or two of hydrogen or hydroxyl;
with the proviso that when R1 is cyclohexyl, then R2 and R3 are limited to hydroxyl or C1-5 alkyl;
R4 is hydrogen, C1-5 alkyl, or C6-10 cycloalkyl;
R5 is hydrogen or acetyl;
or ;
R6 is R7 is , , , , , , , , , , , , , hydrogen, NSO2R12 or NHO-C1-4 alkyl;
R8 is hydrogen or C1-5 alkyl;
R9 is hydrogen or C1-5 alkyl;
R10 is -CH3, , , , or ;
R11 is -CH3, , , , or ;
R12 is hydrogen, C1-5 alkyl or C1-5 alkoxy; and m is an integer of from 0 to 5;
with the proviso that when X is and when R1 is disubstituted phenyl when the phenyl substituents are any of hydroxyl, carboxyl, nitro, halogen, mono-, di- or tri-C1-3 alkyl, C1-5 alkoxy; or when R1 is pyridyl; or when R1 is -CH3 or -CH(CH3)2; or when R1 is unsubstituted bicyclo loweralkyl of 9 carbons or unsubstituted or substituted cyclohexyl and the substituent is hydroxyl; then Y is -(CH2)m- where m has a value of from 1 to 5.
Y is -CO- or -SO2-;
Z is an optional substituent that, when present, is one or more of N, O, S, -CHR-, -CR=CH-, -CH=, -(CH2)m-CHR-, -(CH2)m- or -CHCHOH-;
R is hydrogen, C1-5 alkyl or C1-5 alkoxycarbonylamino, quinuclidinylaminocarbonylamino;
R1 is-CH3,-CH(CH3)2, , , , , , , , , , , , , , -NR4R5 or-NCOR6;
R2 is hydrogen, hydroxy, carboxyl, acetyl, cis or trans oximino, nitro,spirocyclic indenyl, N-spiroindanepiperidinyl, O-Het where Het is imidazole or benzimidazole or azimidobenzene, or where R2 is further defined as -COR6, -(CH2)m-NHCOR7, -(CH2)mNHCOOR7, -(CH2)m-NR8R9, -(CH2)m-NHCO-(CH2)mR7, -(CH2)m-NHCO-CHR7R7, -(CH2)m-NHCO-CH=CHR7, -(CH2)m-CO-O-R7, -(CH2)m-CO-O-(cH2)mR7, -(CH2)m-CO-O-CHR7R7, -(CH)m-CO-O-CH=CHR7, -NHSO2R-where R is as defined above, NHSO2R7, -(CH2)m-O-R10, -SO2R10, -COR11, , , , or or one to two substituents selected from the group consisting of or ;
R3 is one or two of hydrogen or hydroxyl;
with the proviso that when R1 is cyclohexyl, then R2 and R3 are limited to hydroxyl or C1-5 alkyl;
R4 is hydrogen, C1-5 alkyl, or C6-10 cycloalkyl;
R5 is hydrogen or acetyl;
or ;
R6 is R7 is , , , , , , , , , , , , , hydrogen, NSO2R12 or NHO-C1-4 alkyl;
R8 is hydrogen or C1-5 alkyl;
R9 is hydrogen or C1-5 alkyl;
R10 is -CH3, , , , or ;
R11 is -CH3, , , , or ;
R12 is hydrogen, C1-5 alkyl or C1-5 alkoxy; and m is an integer of from 0 to 5;
with the proviso that when X is and when R1 is disubstituted phenyl when the phenyl substituents are any of hydroxyl, carboxyl, nitro, halogen, mono-, di- or tri-C1-3 alkyl, C1-5 alkoxy; or when R1 is pyridyl; or when R1 is -CH3 or -CH(CH3)2; or when R1 is unsubstituted bicyclo loweralkyl of 9 carbons or unsubstituted or substituted cyclohexyl and the substituent is hydroxyl; then Y is -(CH2)m- where m has a value of from 1 to 5.
2. A compound as claimed in Claim 1, wherein X is
3. A compound as claimed in Claim 1, wherein X is
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in Claim 1 sufficient to prevent preterm labor in a mammal in need thereof.
5. A method of antagonizing oxytocin from binding to its receptor site in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
6. A method of preventing preterm labor in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
7. A method stopping labor preparatory to cesarian delivery in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
8. A method of treating dysmenorrhea in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
9. A method of antagonizing vasopressin from binding to its receptor site in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
10. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
11. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
12. A method of inducing diuresis in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
13. A method of inhibiting platelet agglutination in a mammal in need thereof, comprising the step of sdministering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95793892A | 1992-10-07 | 1992-10-07 | |
| US957,938 | 1992-10-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2143117A1 true CA2143117A1 (en) | 1994-04-14 |
Family
ID=25500372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002143117A Abandoned CA2143117A1 (en) | 1992-10-07 | 1993-09-27 | Tocolytic oxytocin receptor antagonists |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0663827A4 (en) |
| JP (1) | JPH08502474A (en) |
| AU (1) | AU5292393A (en) |
| CA (1) | CA2143117A1 (en) |
| WO (1) | WO1994007496A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09500133A (en) * | 1993-07-16 | 1997-01-07 | メルク エンド カンパニー インコーポレーテッド | Substituted piperazinyl camphor derivatives as antagonists of oxytocin |
| AU691829B2 (en) * | 1993-07-16 | 1998-05-28 | Merck & Co., Inc. | Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists |
| US5464788A (en) * | 1994-03-24 | 1995-11-07 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
| US5707985A (en) * | 1995-06-07 | 1998-01-13 | Tanabe Seiyaku Co. Ltd. | Naphthyl-, quinolyl- and isoquinolyl- sulfonamide derivatives as cell adhesion modulators |
| WO1998046569A1 (en) * | 1997-04-11 | 1998-10-22 | Sumitomo Pharmaceuticals Co., Ltd. | Benzene derivatives |
| GB9819860D0 (en) | 1998-09-12 | 1998-11-04 | Zeneca Ltd | Chemical compounds |
| ES2250432T3 (en) | 2000-07-05 | 2006-04-16 | Ortho-Mcneil Pharmaceutical, Inc. | ESPIROBENZOAZEPINAS NON-PEPTIDIC REPLACED, VASOPRESINE ANTAGONISTS. |
| EP1613601A4 (en) | 2003-04-04 | 2007-05-02 | Merck & Co Inc | Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists |
| SI1633719T1 (en) * | 2003-06-17 | 2010-01-29 | Janssen Pharmaceutica Nv | Substituted spirobenzazepines |
| DE102005000666B3 (en) | 2005-01-04 | 2006-10-05 | Sanofi-Aventis Deutschland Gmbh | Sulfonylpyrrolidines, process for their preparation and their use as pharmaceuticals |
| ATE532786T1 (en) | 2006-09-22 | 2011-11-15 | Janssen Pharmaceutica Nv | SPIROBENZAZEPINES AS VASOPRESSIN ANTAGONISTS |
| WO2008036759A1 (en) | 2006-09-22 | 2008-03-27 | Janssen Pharmaceutica N.V. | Spiro benzazepines as vasopressin antagonists |
| WO2008068185A1 (en) | 2006-12-07 | 2008-06-12 | F. Hoffmann-La Roche Ag | Spiro-piperidine derivatives as via receptor antagonists |
| MX2009006454A (en) * | 2006-12-22 | 2009-06-26 | Hoffmann La Roche | Spiro-piperidine derivatives. |
| ATE517866T1 (en) | 2006-12-22 | 2011-08-15 | Hoffmann La Roche | SPIROPIPERIDINE DERIVATIVES |
| US20100022572A1 (en) | 2008-07-18 | 2010-01-28 | Kowa Company, Ltd. | Novel spiro compound and medicine comprising the same |
| WO2011111875A1 (en) * | 2010-03-11 | 2011-09-15 | Dainippon Sumitomo Pharma Co., Ltd. | N-acyl cyclic amine derivative or pharmaceutically acceptable salt thereof |
| US11717499B2 (en) * | 2011-06-28 | 2023-08-08 | Sandra Eve Reznik | Administration of N,N-dimethylacetamide for the treatment of preterm birth |
| JP5715605B2 (en) * | 2011-09-14 | 2015-05-07 | 大日本住友製薬株式会社 | Pharmaceutical comprising N-acyl cyclic amine derivative or pharmaceutically acceptable salt thereof |
| WO2014024993A1 (en) * | 2012-08-09 | 2014-02-13 | 国立大学法人京都大学 | Piperazine derivative and use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8917069D0 (en) * | 1989-07-26 | 1989-09-13 | Merck Sharp & Dohme | Therapeutic agents |
| US5091387A (en) * | 1990-03-02 | 1992-02-25 | Merck & Co., Inc. | Spirocyclic oxytocin antagonists |
| EP0444945A3 (en) * | 1990-03-02 | 1992-05-13 | Merck & Co. Inc. | Use of spirocyclic compounds as oxytocin antagonists |
| EP0445974A3 (en) * | 1990-03-05 | 1992-04-29 | Merck Sharp & Dohme Ltd. | Spirocyclic antipsychotic agents |
| IL99957A0 (en) * | 1990-11-13 | 1992-08-18 | Merck & Co Inc | Piperidinylcamphorsulfonyl oxytocin antagonists and pharmaceutical compositions containing them |
-
1993
- 1993-09-27 AU AU52923/93A patent/AU5292393A/en not_active Abandoned
- 1993-09-27 WO PCT/US1993/009152 patent/WO1994007496A1/en not_active Application Discontinuation
- 1993-09-27 CA CA002143117A patent/CA2143117A1/en not_active Abandoned
- 1993-09-27 JP JP6509222A patent/JPH08502474A/en active Pending
- 1993-09-27 EP EP93923134A patent/EP0663827A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0663827A1 (en) | 1995-07-26 |
| AU5292393A (en) | 1994-04-26 |
| EP0663827A4 (en) | 1995-11-15 |
| WO1994007496A1 (en) | 1994-04-14 |
| JPH08502474A (en) | 1996-03-19 |
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