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WO1999059584A1 - Combinaison de phentolamine et d'inhibiteurs de la phosphodiesterase gmp cyclique utilises dans le traitement des dysfonctions sexuelles - Google Patents

Combinaison de phentolamine et d'inhibiteurs de la phosphodiesterase gmp cyclique utilises dans le traitement des dysfonctions sexuelles Download PDF

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Publication number
WO1999059584A1
WO1999059584A1 PCT/US1999/007046 US9907046W WO9959584A1 WO 1999059584 A1 WO1999059584 A1 WO 1999059584A1 US 9907046 W US9907046 W US 9907046W WO 9959584 A1 WO9959584 A1 WO 9959584A1
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alkyl
group
pharmaceutically acceptable
hydrogen
acceptable salt
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PCT/US1999/007046
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English (en)
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Thomas Mark Estok
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Schering Corporation
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Priority to AU40685/99A priority Critical patent/AU4068599A/en
Publication of WO1999059584A1 publication Critical patent/WO1999059584A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates to pharmaceutical compositions comprising a combination of phentoiamine and cyclic guanosine 3',5 ' -monophosphate phosphodiesterase (cGMP PDE) inhibitors and to methods of treating sexual dysfunction, especially erectile dysfunction, comprising administering an effective amount of a combination of phentoiamine and cGMP PDE inhibitors.
  • cGMP PDE cyclic guanosine 3',5 ' -monophosphate phosphodiesterase
  • compositions and methods of this invention results in an unexpected potentiation of human sexual response.
  • Tne present invention is directed to the use of phentoiamine in combination with cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors for the treatment of human sexual dysfunction.
  • cGMP PDE cyclic guanosine 3',5'-monophosphate phosphodiesterase
  • the invention contemplates the use of Type V cGMP PDE inhibitor in combination with phentoiamine with sildenafil being the preferred Type V cGMP PDE inhibitor.
  • the present invention relates to a method of treating sexual dysfunction, especially erectile dysfunction, comprising administering to a human in need of such treatment an effective amount of a combination of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a cGMP PDE inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • the invention contemplates the use of Type V cGMP PDE inhibitor in combination with phentoiamine, with sildenafil being the preferred Type V cGMP PDE inhibitor.
  • Phentolamine mesylate and sildenafil citrate are the most preferred active ingredients for use in the methods of this invention.
  • the invention in a second aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a cGMP PDE inhibitor, or a pharmaceutically acceptable salt solvate thereof.
  • the pharmaceutical compositions envisioned by the present invention comprise phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a Type V cGMP PDE inhibitor, or a pharmaceutically acceptable salt solvate thereof, with sildenafil being the preferred Type V cGMP PDE inhibitor.
  • Phentoiamine mesylate and sildenafil citrate are the most preferred active ingredients of the pharmaceutical compositions of this invention.
  • the invention in a third aspect, relates to a kit comprising in one container an effective amount of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof in a pharmaceutically acceptable carrier, and in a separate container, an effective amount of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt, solvate thereof in a pharmaceutically acceptable carrier, with sildenafil being the preferred Type V cGMP PDE inhibitor.
  • Phentoiamine mesylate and sildenafil citrate are the most preferred active ingredients for use in the kits of this invention.
  • the invention in a fourth aspect, relates to a pharmaceutical composition for the treatment of human sexual dysfunction comprising a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker. More preferably, the adrenergic blocker is an alpha-adrenergic blocker.
  • the alpha adrenergic blocker is selected from the group consisting of an alphal -adrenergic blocker, an alpha2-adrenergic blocker or both an alphal -adrenergic blocker and an alpha2-adrenergic blocker.
  • the second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP PDE inhibitor.
  • the first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker and the second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP
  • the adrenergic blocker can be selected from the group consisting of phentoiamine, phentoiamine mesylate, phentoiamine hydrochloride, phenoxybenazmine, tolazoline, dibenamine, yohimbine, terazosin, doxazosin, prazosin and the like.
  • the cGMP PDE inhibitor can a cGMP PDE V inhibitor.
  • the cGMP PDE V inhibitor is selected from the group consisting of: sildenafil,
  • the invention in a fifth aspect, relates to a method of treating human sexual dysfunction comprising the simultaneous or sequential administration of a therapeutically effective amount of a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof
  • a pharmaceutically acceptable carrier a pharmaceutically acceptable carrier.
  • Humans include, of course, males and females.
  • pharmaceutical compositions of the present invention are envisaged primarily for the treatment of erectile dysfunction or male sexual dysfunction, they may also be useful for the treatment of female sexual dysfunction.
  • female sexual dysfunction may include orgasmic dysfunction due to clitoral irregularities or disturbances.
  • Phentoiamine, 3-[[(4,5-dihydro-1 H-imidazol-2-yl)methyl](4- methylphenyl)amino]phenol, and pharmaceutically acceptable salts, solvates, hydrates, crystalline polymorph forms and the free base thereof, are useful in the treatment of sexual dysfunction.
  • a rapidly disintegrating tablet and method of use to treat sexual dysfunction is disclosed in United States Patent No. 5,731 ,339, also incorporated herein by reference.
  • Representative formulations comprising phentoiamine are disclosed in U.S. 5,731 ,339.
  • Phentoiamine can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. hemi-hydrate.
  • Phentoiamine can form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for salt formation are hydrohalic acids such as hydrochloric and hydrobromic; as well as other acids such as sulfuric, phosphoric,- acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, toluenesulfonic and other mineral and carboxylic acids known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base form for purposes of this invention.
  • Phentoiamine can also form crystalline polymorph forms or crystalline forms thereof using suitable or conventional crystallization procedures.
  • the present invention is directed to the use of cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors in combination with the salts or esters of phentoiamine, preferably, with phentoiamine mesylate for the treatment of human sexual dysfunction, preferably erectial dysfunction
  • cGMP PDE inhibitors contemplated in this invention are as follows and are described in the following documents, as indicated. The disclosure of each of the below-referred to document is inco ⁇ orated herein by reference. European published application number 0201188, which discloses compounds of the formula
  • R is a lower afkyl of from one to six carbon atoms, a lower alkenyl of from one to six carbon atoms, a lower hydroxyalkyl of from one to six carbon atoms, a lower hydroxyalkenyl of from two to six carbon atoms, a lower aminoalkyl of from one to six carbon atoms, or a lower aminoalkenyi of from two to six carbon atoms;
  • n is 0 or an integer of from 1 to 4;
  • Ar is a radical of the following general formula (R 2 )
  • X, Y, and Z are. independently, (1) hydrogen; (2) lower alkyl of from one to six carbon atoms; (3) halogen, (4) hydroxyl;
  • R' and R" are each, independently, (a) hydrogen or (b) lower alkyl of from one to six carbon atoms optionally substituted by (i) amino, (ii) morpholino or (iii) cycloalkyl of from, five to seven carbon atoms; (9) sulfonyl; or
  • A represents a group of formula:
  • R * and R-" are the same or different and each represents a hydrogen atom, a halogen atom or a group of formula -OR';
  • R' and R' are the same or different and each represents a carbamoyl group or a carboxy group:
  • R' and R' both represent hydrogen atoms or together they represent an extra carbon-carbon bond between the carbon atoms to which they are attached;
  • R' represents a hydrogen atom, a halogen atom or a group of formula -OR'. -NR"R * ' or -SR';
  • R* represents a halogen atom or a group of formula -OR', -NR' ⁇ R" or -SR';
  • R * represents a hydrogen atom, a C,-C» alkyl group, an alkylsulphonyl group, a haloalkylsul- phonyl group, an arylsulphonyl group or a hydroxy- protech ⁇ g group;
  • R" and R" are the same or different and each
  • R" and R.” together represent a substituted methylene group, or R *** and R", together with the nitrogen atom to which they are attached, represent a heterocyclic group having 5 or 6 ring atoms, of which, in addition to the nitrogen atom shown, 0 or 1 are additional oxygen, nitrogen or sulphur heterc-atoms, said heterocyclic group being unsubstituted or having from 1 to 3 C- C alkyl and/or C,-C « alkoxy subs ⁇ tuents;
  • R" represents a C,-C « alkyl group
  • Z represents a hydrogen atom, a hydroxy group or a substituted hydroxy group
  • W represents an alkoxy group or an aralkoxy group; provided that, when A represents said group of formula (e), R* and R * both represent hydrogen atoms; and pharmaceutically acceptable salts and esters thereof.
  • Preferred compounds include:
  • A represents a group of formula:
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom or a group of formula -OR 9 ;
  • R 3 and R' are the same or different and each* represents a artiamoyl-group'or a carboxy group
  • R s and R 6 both represent hydrogen atojns
  • R 3 represents a hydrogen at ⁇ rr a Ci -C ⁇ alkyl group, an alkylsulphonyi group, a haloalkylsulpho ⁇ yl group, an arylsulp o ⁇ y! group or a hydroxy-protecti ⁇ g group;
  • R 1Z represents a C ⁇ -C « alkyl group; and pharmaceutically acceptable salts and esters thereof. 59584
  • R 1 is Ci.s3lkyl.or C 2 ,jalkenyl. and R 2 is hydrogen or hydroxy.
  • Preferred compounds include: 2-(2-ethoxyph ⁇ nyl)-6-purinone.
  • R' is C.-salkyl, C_- ⁇ * alkenyl. C -scycloalkylCi -talkyi. or C ⁇ -*.al yl substituted by 1 to 6 fluoro groups:
  • R * - is hydrogen, -CN, -CONR 5 R 6 , -COzR', 5-tatrazolyl, -N0 2 , -NHj or -NHCOR 8 wherein R 5 , R E , B? and
  • R 8 are Independently hydrogen or Ci-ialkyl
  • R 3 is hydrogen or Ci - ⁇ alkyl
  • R* is hydrogen or C ⁇ - «alkyl: wfth the proviso that R ! is not methyl when R 2 is -CO.H, -COzCH z CH 3 or -CN.
  • X is 0, R 3 Is hydrogen and
  • R* is hydrogen or methyl.
  • Preferred compounds include:
  • 6-(2-propoxyphenyl)-1 ,2-dihydro-2-oxopyridine-3-carboxylic acid methyl 6-(2- ⁇ ropoxyphenyl)-1 ,2-dihydro-2-oxopyridine-3-carbo ⁇ ylate.
  • R 1 is C - ⁇ alkyl, Cs-ealke ⁇ yl, C 3 -scycloalkylC ⁇ - «alkyl, or Ci -salkyl substituted by 1 to 6 fluoro groups;
  • R z is Ci - ⁇ alkylt io, Ci -salkylsulphonyl, Ci - ⁇ alkoxy, hydroxy, hydrogen, hydrazino, Ci-salkyl, phenyl, -NHCOR 3 wherein FI 3 is hydrogen or d- ⁇ alkyl, or - R * -R S wherein R* and R 5 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, hexahydroazepi ⁇ o.
  • R + and R s are independently hydrogen, Cj-s cycloalkyl or Ct-s alkyl which is optionally substituted by -CF 3 , phenyl, -S(0) ft C ⁇ - ⁇ alkyl wherein n is 0, 1 or 2, -OR 5 , -C0 2 R ? or -NR ⁇ R 3 wherein R 5 to R 3 are independently hydrogen or Ci-ealkyl, provided that the carbon atom adjacent to the nitrogen atom is not substituted by said -S(0) trustC ⁇ - « alkyl, -OR 5 OF--NR 8 R 9 groups; and R is hydrogen and can also be hydroxy when R 2 is hydroxy.
  • Preferred compounds include:
  • X is oxygen or sulphur
  • R 1 is Ci - ⁇ alkyl, C 2 - €alkenyl, Ca-scycloalkylCj -*alkyl, or C ⁇ - «.alkyi substituted by 1 to ⁇ fiuoro groups,
  • Preferred compounds include:
  • R * is Ci - ⁇ alkyl, C2- E alk9nyl, C3-scyc [ oalkylC,-salkyl, or Ci - ⁇ aikyI substituted by 1 to 6 fiuoro groups;
  • R 2 is Ci - ⁇ aikylthio, Ci -s alkylsulphonyi, C ⁇ - ⁇ aikoxy, hydroxy, hydrogen, hydrazino, Ci - ⁇ alkyl, phenyl, • NHCOR 3 wherein R 3 is hydrogen or Ci -salkyl, or -NR'-R * -, wherein R * - and R 5 together with the nitrogen atom to which they are attached form a pyrroiidino, piperidino, hexahydroazeptno, morpholino or piperazino ring, or R* and R 5 are independently hydrogen, Ca -5 cycloalkyl or Ct - ⁇ alkyl which is optionally substituted by -
  • Preferred compounds include:
  • R 2 is hydrogen, hydroxy, C ⁇ -*aJkyl, phenyl, mercapto, C,-,alkylthio, CF, or amino;
  • R 3 is hydrogen, nitro, amino, Ci - alkanoyiamino, C t -+-alkoxy, C ⁇ -+alkyl. halo,' SOa R ⁇ R* CONR*RS cyano or C ⁇ - 4 alkyIS ⁇ 0) ⁇ ; '
  • R* and R 5 are independently hydrogen or d- H aJkyf; and Preferred compounds include:
  • 1 is Oi- ⁇ alkyl, Ca- g alkenyl, C 3 - s cydoalkylC ⁇ - ⁇ alkyl, ph ⁇ nylC, -*alkyl or Ci - ⁇ alkyl substituted by 1 to 6 fiuoro groups;
  • R 2 is hydrogen, Ci-talkyJ, Ci-salkyfthio, Ct -.alkoxy. nftr o or - RW;
  • R 3 and R* are independently hydrogen or Ct - ⁇ alkyl optionally substituted by hydroxy provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy; with the proviso that R 1 is not methyl or ethyl when R 2 Is hydrogen. /59584
  • Preferred compounds include:
  • R" is Ci - ⁇ aJkyl, C 2 - 6 alkenyI, C 3 -scycloalkylCt - ⁇ alkyl, phenylCi - ⁇ alkyl or Ci -.alkyl substituted by 1 to 6 fiuoro groups;
  • R 2 is C, -.alkyl, phenyl, hydroxy, C, - 6 alkoxy, halo.
  • -NHCOR 3 . -NHCONHR * - . S-tetrazolyl, -C0 2 R s . cyano,
  • R 3 to R 7 are independently hydrogen or Ci -salkyl and R 8 and R 3 are independently hydrogen or Ci -sallcyl optionaily substituted by hydroxy provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy;
  • Preferred compounds include: e-amlno-2-(2-propoxyph ⁇ nyl)pyrimidin-4 ⁇ 3H]-one,
  • A is N or CH
  • B is N CRs
  • D is N or CR 2 ;
  • R, R I are the same or independently hydrogen, hydroxy, loweralkyl, lower alkoxy, phenyloxy, R G S(0) n -, W-
  • R ⁇ is hydrogen, lower alkyl, phenyl which may be substituted by up to three methoxy groups, lower alkyl substituted by phenyl which may be substituted by up to three methoxy groups, - lower alkyl -N(R B )2,
  • R3 is hydrogen, lower alkyl, phenyl, lower alkylphenyl, pyridinyl or loweralkyl pyridi ⁇ yl;
  • R*., Rs are the same or independently hydrogen or lower alkyl
  • Hs is lower alkyl, phenyl, lower alkylphenyl or pyridinyl
  • R7 are the same or independently hydrogen, loweralkyl, phenyl. pyridinyl.
  • Ra are the same or independently lower alkyl, phenyl or pyridinyl;
  • Q is -0-, -N-, -CHjO- or -CH j N- R, R,
  • W is hydroxy, loweralkoxy, phenoxy, -N(R w ) j . — J — N x
  • ALK is a Ci-Ct straight or branched chain alkyl
  • Rs is hydrogen, lower alkyl or phenyl
  • Rio are the same or independently hydrogen, loweralkyl or phenyl
  • R1 are the same or independently hydrogen or lower alkyl
  • X is -CH2-. -0-.
  • Preferred compounds include:
  • R 1 is C»- «alkyl.
  • Preferred compounds include:
  • X is O or S
  • R 1 is Ci -.alkyl, Cj-salkenyl, C--scycloalkylC, - «alkyl, or C alkyl substituted by 1 to 3 fiuoro groups;
  • R 2 is hydrogen, -CN, -CONR'-R 6 , -C ⁇ 2R 7 ,5-tetrazolyl. -N0 2 , -NH 2 or -NHCOR 8 wherein R 5 to R B are independently hydrogen or Ct -+alkyi;
  • RF 3 is hydrogen or C ⁇ -*alkyl
  • R *1 is hydrogen or Ci - ⁇ aJkyl
  • R is halo, C ⁇ -*alkyl. C,-*alko ⁇ y, cyano, -CONR 9 R'°, -C0 2 R", -S(0) n C ⁇ - ⁇ all ⁇ yr. -N0 2 , -NH 2 , -NHCOR 12 . or
  • n 0, 1 or 2 and R 1 to R ,+ are independently hydrogen or C ⁇ - alkyl; with the proviso that R 1 is not methyl when R- * is -C0 2 H, -C ⁇ 2CH>CHvisor or -CN, X is 0, R 3 is hydrogen, R 4 is hydrogen or methyl and R is 6-methoxy.
  • Preferred compounds include:
  • R is halo.
  • £> ' is a ring ⁇ f sub-formula (a) or (b)
  • R 1 is hydrogen or C,_» alkyl
  • Y is a single bond or C _e alkylene
  • R° is hydrogen, C 1-t alkyl, hydroxy-C, ⁇ alkyl or -CyA-(R 2 )), * R 1 ⁇ and R 17 independently are hydrogen or C ⁇ alkyl; p is 0-2; CyAis
  • R 2 is (1) hydrogen, (2) C 1-4 alkyl, (3) C 1-4 alkoxy, (4) -COOR 6 , in which R 6 is hydrogen or C ⁇ alkyl, (5) -NR ⁇ R 7 , in which R ⁇ and R 7 Independently are hydrogen or C,_, alkyl, (6) -S0 2 NR 8 R 7 , in which R* and R 7 are as hereinbefore defined, (7) halogen, (8) frifluoromethyl, (9) nitro or (10) trifluoromethoxy; Z is a single bond, methyle ⁇ e, ethylene, vi ⁇ yle ⁇ e or ethy ⁇ yle ⁇ e; CyB is
  • R* is hydrogen, C ⁇ alkyl, C,_ « alkoxy, halogen or trifluoromethyl; * •
  • R-* is (1) hydrogen, (2) C,_ « alkyl, (3) C ⁇ alkoxy, (4) -COOR 8 , in which R s is hydrogen or C 1-4 alkyl, (5) -NR B R 10 , in which R fl is hydrogen.
  • R- 4 is hydrogen or C,.* alkyl or phenyl(C 1 ⁇ alkyl) and R' ⁇ is C, ⁇ , alkyl or (17) C ⁇ alkylthto. (18) C ⁇ alkylsulfinyl, (19) Ci.* alkyisutfo ⁇ yl.
  • CyA-fR ) ! does not represent cydopentyl or frif luoromethylphenyl when Y is a single bond
  • CyB is not pyridine or thiophene when CyA is a 4-7 membered unsaturated, partially saturated or fully saturated heterocyde containing one ortwo oxygen atoms, and
  • Y Is not a single bond when A is ( ⁇ ) -0-R» or -S(0) p -R° or (iii) -NR ⁇ «R"; or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • Preferred compounds include:
  • R 1 represents arylmethyl or C, - ⁇ , alkyl optionally substituted by one or more fluorine atoms
  • R 2 represents methyl
  • R ? represents C? -.alkyl
  • R- 1 represents nitro, cyano, C, - E alkoxy.
  • C( X)NR 5 R 7 .
  • R* may also represent hydrogen
  • R 5 represents hydrogen or C ⁇ - «alky(
  • R c represents hydrogen or C ⁇ -6alkyl
  • R 7 represents hydrogen, amino, hydroxyl, Ci - 6 alkyl, aryl or arylCi - ⁇ alkyl;
  • R 8 represents hydrogen or C ⁇ - « alkyl
  • R 10 represents hydrogen or Ci -salkyl
  • R 11 represents Ci -salkyl optionally substituted by one or more halogen atoms, or R n represents aryl, arylCi -.alkyl, thienyl, NR ls , ⁇ , CH 2 NR ,7 R 18 or R'° and R" together represent -A(CH Z ) deliberately-;
  • R 12 represents Cj -. alkyl, aryl or arylCi -.alkyl
  • R' 3 represents hydrogen or & -c alkyl
  • R" represents hydrogen, C, --, alkyl. aryl. arylC, -.alkyl or R» and R" together with the nitrogen atom to which they are attached form a morpholine.
  • piperazine or N-C-.alkylpiperaz.ne ring R « represents hydrogen or C, - ⁇ *alky! or R'° and R 15 together represent -A(CH,) n - R" represents hydrog n, C -.alkyl. aryl. arylCi -.alkyl. CCfeR".
  • R 17 represents hydrogen or Ci - ⁇ alkyl: ...
  • X represents S or NH, or when R 7 represents amino then X may also represent O; Y represents O or S; for use in therapy.
  • Preferred compounds include:
  • A is a bond, C1-4 alkylene or C1-4 oxyalkyiene; is a bond, C1-4 alkylene, C1-4 alkyleneoxy, C1-4 alkoxyphenylene or phe ⁇ yl(C1-4)alkyle ⁇ e;
  • Z is a bond or vinyle ⁇ e
  • R1 Is 4-15 membered heterocyclic ring containing one ortwo nitrogen atoms optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl and ⁇ itro;
  • R2 is (i) 4-15 membered heterocydic ring containing one ortwo hetero atoms chosen from nitrogen, oxygen, and sulphur, not more than one hetero atom being sulphur, optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, ⁇ itro and groups of formula:
  • R10 is hydrogen or C1-4 alkyl, (ii) C4-15 carbocydic ring, (iii) C1-4 alkoxy, (iv) hydroxy(C1-4 alkoxy) or (v) hydroxy;
  • R3 is (i) 4-15 membered heterocydic ring containing one ortwo hetero atoms chosen from nitrogen, oxygen and sulphur, not more than one hetero atom being oxgen or sulphur, optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, nitro, cyano, ethynyl and groups of formula;
  • CH2 CH(X)- wherein X is halogen, or (iv) hydrogen, and I is 1 or 2, provided that R2 Is not hydroxy when Y is a bond; R1 is not bonded through its nitrogen atom when Z is vi ⁇ ylene; and exduding compounds of the formula:
  • R*- * - is methyl or n-propyl
  • R 66 is cydopentyl, cyc ihexyl, 2-hydroxyethyl, methoxyethyl, 2-(1-piperWinyl)ethyl, or phenyl or benzyl which may be substituted by 1 or 2 of methyl, methoxy, chloro, nitro and trifluoromethyl;
  • R 00 is hydrogen or methyl
  • R°° is methyl or n-propyl, isopropyl or benzyl; and ⁇ is hydrogen or methyl; and th
  • R 1 and R 2 are the same or different and represent hydrogen, lower alkyl (which is optionally substituted with one to three substrtuents which are the same or different and are cydoalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted ammo, nitro, halogen, alicyclic heterocyde group (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aralkyl, aryl optionally substituted with one to three substituents which are the same or different and are lower alkoxy, or aromatic heterocyde group)), cycloalkyl, btcycloalkyl, benzocycloalkyl (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl,
  • R 1 and R z are taken together to represent heterocyde group containing nitrogen atom (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aryl, or aralkyl),
  • R 3 represents hydrogen, lower alkyl (which is optionally substituted with one to three substituents which are the same or different and are cydoalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, halogen, or alicyclic heterocyde group (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aralkyl, aryl optionally substituted with one to three substituents which are the same or different and are lower alkoxy.
  • aromatic heterocyde group (where said aromatic heterocyde group part is optionally substituted with one to three substituents which are the same or different and arc lower alkyl, hydroxy, lower alkoxy, carboxy.
  • aromatic heterocyde group where said aromatic heterocyde group Is optionally substituted with one to three substrtuents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, sulfonamide, halogen, or trifluoromethyl
  • aromatic heterocyde group where said aromatic heterocyde group Is optionally substituted with one to three substrtuents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, sulfonamide, halogen, or trifluoromethyl
  • aralkyl where the aryl part of said aralkyl is optionally substituted with one to three substrt
  • R ⁇ R 2 , R 3 , R* and R 5 may be the same or different from each other and each represents a hydrogen atom, a haioge ⁇ atom, a lower alkyl group or a lower alkoxy group;
  • R ⁇ and R 7 may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, a lower alkoxyalkyl group, a cyanoalkyl group, a heteroarylalkyl group, a cycloalkyl group, a cydoalkylalkyl group or a carboxyl alkyl group which may be protected, or alternatively R- * and R 7 may form a ring together with the nitrogen atom to which they are bonded, this ring optionally having a substituent). or a pharmacologically acceptable salt thereof:
  • WO91/19717 discloses compounds of the formula
  • J oxygen or sulfur
  • R 1 is hydrogen, alkyl or alkyl substituted with aryl or hydroxy
  • R 2 is hydrogen, aryl, heteroaiyl, cycloalkyl, alkyl or alkyl substituted with aryl, heieroaryf, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamlno, or -(CH2)mTCOR 20 wherein m is an integer from 1 to 6, T is oxygen or-NH- and R 2 " is hydrogen, aryl, heteroaryf, alkyl or alkyl substituted with aryl or heter ⁇ aryl; R 3 is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkyiami ⁇ o, dialkyiamino, hydroxyalkylamino, aminoalkyla ino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkyi
  • Ra, R b , e and R d independently represent hydrogen, alkyl, cycloalkyl or aryl; or (R a and R b ) or (R c and R d ) or (Rb and R c ) can complete a saturated ring of 5- to 7- carbon atoms, or (Ra and R b ) taken together and (R b and R c ) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following:.
  • Preferred compounds include: cis-5,6a,7,8 7 9,9a-Hexahydro-5-methyl-3-(phenylmethyl)- cyclope ⁇ ta[4,5]imidazo[2,1-b]purin-4-one; 7,8-Dihydro-5-methyl-3-(phenylmethyl)-3W-imidazo[2,1 ⁇ b]purin-4(5r)- one; ds-6a,7 f 8,9,10,10a-Hexahydro-5-methyl-3-(phe ⁇ ylmethyi)-3H- be ⁇ zimidazo[2,1-b] purin-4(5 -/ ⁇ -one; 5,7,8,9-Tetrahydro-5-methyi-3-(phenylmethyl)pyrimjdof2,1-b]purin-
  • WO 94/19351 discloses compounds of the formula
  • R , R 2 and R 3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di- lower atkyl)amino, 4-morphoIinyl, 1-pyrrolidinyl, 1-pyrrolyl, -CF 3 , -OCF 3, phenyl and methoxyphenyl; or Ri and R 2 together are methylenedioxy; or Rt and R2 together with the carbon atoms to which they are attached form a benzene ring; and
  • R a is hydrogen and R b and R c , together with the carbon atoms to which they are attached,. form a saturated ring of ⁇ carbons; or R a is lower alkyl, R is hydrogen or lower alkyl, and R c is hydrogen; or R a , R and the carbon atom to which they are attached form a saturated ring of ⁇ - 7 carbons, and R c is hydrogen; or R a is hydrogen, and R b , R c and the carbon atoms to which they are attached form a tetrahydrofuran ring; or R a and R , together with the carbon atom to which they are attached, and R and R c , together with the carbon atoms to which they are attached, each form a saturated ring of ⁇ -7 carbons.
  • Preferred compounds include:
  • WO 94/22855 discloses compounds of the formula
  • ring* A represents a benzene, pyridine or cyclohexane ring and B represents a pyridine, imidazole or pyrimidine ring, with the proviso that rings A and B are bonded to each other with two atoms b eing shared by them, and the shared atoms may be any of carbon and nitrogen atoms;
  • R 1 represents a group represented by the formula: -NR 4 R 5 (wherein R 4 and R 5 may be the same or different from each other and each represent a hydrogen atom, a lower alkyl or acyl group or a carboxyl group which may be protected, or alternatively R' * and R ⁇ may form a ring together with the nitrogen atom to which they are bonded, provided that the ring may be substituted), or a heteroaryl group which has one or two nitrogen atoms and may be substituted:
  • R- * represents a hydrogen atom, a group represented by the formula:
  • R 8 represents a carboxyl or tetrazolyl group which may be protected
  • R 8 represents a carboxyl or tetrazolyl group which may be protected
  • R 3 represents a hydrogen atom or a group represented by the formula:
  • R B and R 7 each represent a hydrogen or halogen atom or a lower alkoxy group, or alternatively R ⁇ and R 7 may together form a methylenedioxy or ethylenedioxy group ) .
  • R° represents hydrogen, halogen or C-j-e a,k y
  • R represents hydrogen, C-j- ⁇ alkyl, C ⁇ s alkenyl, C 2 * alkynyl, aloC- j . ealkyl, C3_scycloalkyl, C3 driving ⁇ cycloalkylC 1 ..3alkyf, arylC ⁇ alkyl or heteroarylC-
  • R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thi ⁇ phene, furan and pyridine or an optionally
  • substituted bicyciic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a ⁇ - or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R 3 represents hydrogen or C M alkyl, or R ⁇ and R 3 together represent a 3- or 4- membered alkyl or alkenyl chain.
  • Preferred compounds include:
  • R 1 is hydrogen, alkyl, G « to C7 cycloalkyl, C-» to C 7 cycloalkyl substituted by C- to Cjo alkyl or hydroxyl, 2- or 3-tetraiydrofura ⁇ yl, 3-tct ⁇ ahydrothie- nyl 1,1, -dioxide, C4 to C7 cycloalkyl-Ci to Cjb alkyl, carboxy-C- to Cjo lkyL carbo-Ci to G» k>w- er-alkoxy-Cj to Cio alkyl, diallcylainino Cj to C1 0 •lkyl, phenyl-Ci to lower-alkyl, phenyl-Ci to C lower-alkyl in which the phenyl ring it substituted in the 2, 3, or -position by one or two substituents, the twine or different, selected from the group consisting of a ino, halogen, to Cioal
  • R 3 is, Ci to Ci lo ei-alkyl, phenyl-C- to C « loweralkyl, kiwcr-alkoxyphenyl-Ci to lo er-alkyl, diCi to C* io er-alkoxy-phenyl-C] to C4. loweralkyl, pyridyl-Cj to C lowcr-alkyl, to C 7 cy- cloalkyl-C) to QIower-alky p ⁇ enylami ⁇ o, diCj to Cioalky nuno, halogen, trifl ⁇ oromethyl, Ci to C* lower-alky lth ⁇ o, cyano or nitro- and
  • R e is a nine or ten membered bicyclic .ring having carbon and from one to two nitrogen atoms, and -43-
  • thc heterocyde is made up of fused 5 or 6 membered rings or such ring substituted at any available carbon atom by one or two substituents, the same or different, selected from the group consisting of Ci to C + lower-alkyl, halogen, Ci to C lower- alkoxy, C to C7 cycloalkyloxy, -morpholi ⁇ yl, C j to lower-alkoxy-C[ to C ⁇ lower-alkoxy, hy- droxy, imidazolyl, oxo and 4-morpholinyl-C* to C J , lower-alkoxy, or at any available nitrogen atorn by Ci to C* lowcr-alkyl, C 2 to C4 lower-alkanoyl, or trifhioroacetyl; or a pha ⁇ naceuticAlly acceptable acid-addition salt thereof.
  • R-, R 2 , R3 and R 4 have the following meanings: R-: C2-C ⁇ -aIkenyl, Cz-Cts-alkynyl, hydroxy, Cj-C ⁇ - alkoxy, Cj-C ⁇ -alkenyl ⁇ xy, C3-C «-alkynyloxy, Cz-Cfi-alkaaoyloxy, benzoyloxy, morphoUnocar- bonyioxy, Ci-Ce-alkyloxycarbonyloxy, Q-C ⁇ - al ylaminocarbonyloxy, Ci-C f i-dialkylaminocar- bonyloxy or the group
  • Alk is -C ⁇ -alkyf, C ⁇ -C ⁇ -hydroxyalkyl or C-j-Cfi-cycloalkyl and the symbol A represents:
  • Rf and R may be the same or different and represent hydrogen, C ⁇ -C «-fllky ⁇ , Cj-C7-cy oalkyl, C 3 -C 7 -hyd ⁇ raycycloaIkyi, mor- phoIino-Ci-Cs-alkyl, phenyl, phenyl-Ci-Ce-alkyl orphenyl-Cz-Ce-oxyalkvl, it also being possible for the phenyl radicals in R5 and Re to be substituted by halogen and R is hydrogen or Q
  • D is phenyl, Ci-C ⁇ -alkyl, C 3 -G -cycloalkyl, hydroxy, Ci-cValk ⁇ xy, Cj-C-T-pycloalkyloxy, .
  • morpholino, pyrrolidino, piperidino, homopiperid o, piperazino, — NHRj or — NR5R0 and R5 and e have the meanings given herein- above; 4
  • n can be the integers 1-3 and E represents CH_, oxygen, sulfur, NH, CHOH, CH— Ci-C ⁇ - alkyloxy, CH— Ci-Ce-alka ⁇ oyloxy, CH Hj, CHCOA CH— CH 2 QSH5, N— Cj-C ⁇ -alkyl, N— -C ⁇ -hydroxyalkyl, N— C ⁇ Hs,
  • R5 represents pheayL Ci-Cj-alkosyphenyl or diphenylmethyl and R 3 and Rj are hydrogen, and their physiologically acceptable acid addition salts and quaternary ammonium salts, with the exception of the compounds of Formula 1 where R j is methyl, dimefhylaminopropyi, dimetrrylan ⁇ io- ethyl, orpholi ⁇ oethyl or py ⁇ rolidinoethyl, R & R3 and R* are hydrogen and the benzo ring does not contain a nitrogen atom instead of a CH group.
  • R 1 is hydrogen or Cl- alkyh Y is single bond or Cl-6 alkylene;
  • A is
  • ROA is _CyA— (R2)J.
  • ROB is hydrogen or Cl-4 alkyl; p is 0-2; CyA is (1) 3-7 membered, saturated or unsaturated, mono- cyclic carbocyclic ring, (2) 7-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one nitrogen atom, one nitrogen and one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogen and two oxygen atoms,
  • R2 i ⁇ " or R 2 B; - ⁇ is (1) — NR «ARH in which R* A and TM independently are hydrogen or Cl-4 alkyl (with the proviso that R 6 - * * and R 1 are not hydrogen at same time), in which R ⁇ and R 7 independently are hydrogen or CJ-4 alkyl, (3) trifluoromethyl or (4) trifluoromethoxy; ⁇ is (1) hydrogen, (2) Cl-4 alkyl, (3) Cl-4 alkoxy, (4) — COOR s , in which S is hydrogen or Cl-4 alkyl (5) halogen, (6) nitro ⁇ r ⁇ 7) — NRGBR , in which R 6fl and R' ⁇ are hydrogen;
  • 2 is 2 ⁇ or 2J>
  • R 3 is hydrogen, Cl-4 alkyl, Cl-4 alkoxy, halogen or trifruoromethyl; ⁇ is R-t-Or R * "; -" is (1) — NHSO2R", in which R « is Cl-4 alkyl, (2) SO2 R 9 1 0 , in which
  • Ri' is as hereinbefore defined, (7) halogen, (8) trifluoromethyl, (9) nitro, (10) cyano, (11) Cl-4 alkylth t o, (12) Cl ⁇ l- alkylsulfinyl, (13) Cl-4 alkylsnlfo- nyl, (14) hydroxymethyl, and 1, m and n independently are 1 or 2; with the pro ⁇ iso that
  • CyB ring is not pyridine or thiophene when CyA is a ring of C A— (7) that
  • A is not — CyA- ⁇ -(R 2 B)l and — OR 0B , when Z is Z ⁇ a ⁇ d R + is ** 5 ; or pharmaceutically acceptable acid addition salts thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
  • Preferred compounds include:
  • RI, R3, and R4 each of which may be the same or different from each other, may each represent a hydiogcn atom, a halogen atom or a lower alkyl group or a lower alkoxy hydrogen atom, R2 is a halogen or cyan group RS is a group represented by the formula:
  • R61 represents a carboxyl group which may be protected or a heteroaryl group; or R5 is a group rcprcscnted'by the formula;
  • R6 is a group represented by the formula
  • X is hydrogen atom or a halogen atom
  • Preferred compounds include:
  • WO 94/29277 discloses compounds of the formula
  • Ar is an optionally substituted aryl or heteroaryl ring selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazi ⁇ yl, pyrazinyl, inridazolyl, thienyl, oxazolyl, ben2imidazolyl, benzoxazolyl, indolyl or thianaphthenyl, Xis CH orN;
  • R° is NR ⁇ R 2 or hydrogen; and R 1 and R 2 are independently hydrogen or Ci.galkyL
  • Preferred compounds include:
  • R° represents hydrogen, halogen or C ⁇ s'kyl
  • R 1 represents hydrogen, Chalky!, C alkenyl, Cj alkynyl, haloC-
  • R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally
  • substituted bicyclic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R 3 represents hydrogen or C M alkyl, or R 1 and R 3 together represent a 3- or 4- membered alkyl or alkenyl chain.
  • Preferred compounds include:
  • WO 96/28429 discloses compounds of the formula
  • R 1 is tert-butyl, or cydopentyl
  • R 3 is methyl, ethyl, or phenylmethyl ; ,X is -CH2-, -0-, or -NH-; and
  • R 6 is phenyl (or phenyl substituted by from one to three, the same or different, substituents selected from the group O 99/59584
  • Preferred compounds include: l-cycl ⁇ pentyl-3-ethy -6- ( 4-methoxyphenylmethyl)pyrazolo C3,4-d]pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- (4-hydroxyphenylmethyl)pyrazolo [3 , 4-d]pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- (phenylmethyl)pyrazolo[3, 4-d] pyrimindin-4-one, and l-cyclopentyl-3-ethyl-6- (4-aminophenylmethyl)pyrazolo [3, 4-d]pyrimindin-4-one.
  • WO 96/28448 discloses compounds of the formula
  • R 1 is tert-butyl, or cydopentyl ;
  • R 3 is lower-alkyl, or phenyl - lower-alkyl , • and R 6 is phenyl, or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, lower-alkyl, hydroxy, 1-imidazolyl, lower-alkenyloxy, dilower-alkylamino-lower-alkoxy , 4-m.orpholinyl - lower-alkoxy, lower-alkoxycarbonyl-lower-alkox , carboxylower- alkoxy, tri luoromethyl, 1 -piperidinyl - lower-alkoxy , 1- pyrrolidinyl-lower-alkox , nitro, halo, amino, - ⁇ CH 2 )2 ⁇ -, lower- alkyl ⁇ ulf onylamino,
  • Preferred compounds include:
  • R° represents hydrogen, halogen or C-j_5 alkyl; R is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • phenyl optionally substituted by one or more substituents selected from -OR a , -NR a R b , halogen, hydroxy, trifluoromethyl, cyano and nitro;
  • R a and R b independently represent hydrogen or C h alky!.
  • Preferred compounds include:
  • WO 96/32379 discloses compounds of the formula
  • R 1 is hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, cyano, hydroxy rnino (lower) alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with protected carboxy, carboxy or hydroxy;
  • R 2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy;
  • R 3 is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent (s) selected from the group consisting of
  • aryl optionally substituted with one.or more substituent (s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and
  • R 4 is carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl; in addition to their significances above,
  • R 1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7- me bered carbocydic ring optionally substituted with oxo, or its pharmaceutically acceptable salt.
  • WO 97/03070 discloses compounds of the formula
  • R * is a hydrogen atom or a halogen atom
  • R 2 is a phenyl-lower alkyl group
  • R 3 is a heterocyclic group selected from the group consisting of an indolyl group, indolinyl group, IH-indazolyl group, 2(lH)-quinolinonyl group, 3,4- dihydro- ( 1H)-quinolinonyl group and 3 ,4-dihydro- l,4(2H)-benzoxazinyl group, said heterocyclic group may have 1 to 3 substituents selected from the group consisting of: a group of the formula -B-R*, (B, is a lower alkylene group; R* is a 5- to 11-membered saturated or unsaturated heterocyclic group of single ring or binary ring, having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom, (said heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and
  • A is a lower alkylene group; and n is 0 or 1 ,
  • Preferred compounds include: l-Benzyl-6- ⁇ hloro-2- ⁇ l-[3-(imidaz ⁇ l-l- yl ) propyl ] indol ⁇ 5-ylaminocarbonyl > be zimidazole , l-Benzyl-6-chloro-2- ⁇ l-[3-(N-cyclohexyl-N- methylamino ) propyl ] indol-5-ylami nocarbonyl > - benzimidazole . l-Benzyl-6-chloro-2- ⁇ i- [ 3- (pyraz ⁇ l-1- yl )propyl ]indol-5-ylaminocarbonyl ⁇ benzimidazole .
  • WO 97/03675 discloses compounds of the formula
  • R° represents hydrogen, halogen or C-j-o alkyl
  • R 1 represents hydrogen, Chalky), C 2 - 6 alkenyl, C z ⁇ alkynyl, haloCi ⁇ al yl, C3_8cycloalkyI, C3_8cycioalkylC-
  • R 2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic
  • fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and
  • R 3 represents hydrogen or C,. 3 alkyl, or R 1 and R 3 together represent a 3- or 4- membered alkyl or aikenyl chain; for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.
  • Preferred compounds include:
  • R° represents hydrogen, halogen or C-j_6 alkyl
  • R1 represents hydrogen or C-j_ealkyl
  • R 2 represents the bicyclic ring
  • R 3 represents hydrogen or C ⁇ alkyl.
  • Preferred compounds include:
  • R represents -hydrogen or -halogen
  • R 1 is selected from the group consisting of:
  • Het represents 5- or 6-membered heterocyclic group as defined above,
  • Het represents a 5- or 6-membered O 99/59584 -64- heter ⁇ cyclic group as defined above,
  • Het represents a 5- or 6- membered heterocyclic group as defined above
  • R 2 is selected from the group consisting of:
  • R 1 and R 2 together form a 3- or 4- membered alkylene or afke ⁇ ylene chain , opti ⁇ alfy containing at least one heteratom ;
  • R 3 is selected from the group consisting of:
  • R 4 is hydrogen, or R 3 and R 4 together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;
  • R" and R" which may be the same or different, are independently selected from hydrogen and Chalky!.
  • J oxygen or sulfur
  • R 1 is hydrogen, alkyl or alkyl substituted with aryl or hydroxy
  • R 2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl; hydroxy, alkoxy, amino, monoalkyl amino or dialkyiamino, or — (CI mTCOR 20 wherein m is an integer from 1 to T is oxygen or — NH— aad R- ⁇ is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;
  • R 3 is hydrogen, halo, trifluoromethyl, alkoxy, alkyl- ihio, alkyl, cycloalkyl, aryl, a ⁇ ios ⁇ lfbayl, amino, monoaU ylan ⁇ io, dialkyiamino, hydroxyalk- ylamino, aminoalkylamino, carboxy, alkoxycarbonyl or a iaocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, m ⁇ oalkyla ⁇ tmo or dialkyUmino;
  • Preferred compounds include: cis-5,6a,7,8,9,9a-Hexahy ro-5-meihyl-3-(ph-* ⁇ yl e- thyl)cyclopenta[4,5]imidazo[2,l-b]purin-4-o-te; 7,8-Dihydro-5-mettayl-3-(phenyl* * net * hy!>3H- imidazo [2, 1 -b]purin-4(5 H -oae; cis-6a,7,8,9, 10, 10a-Hcx hydro-5-methyl-3-(ph «nyI ⁇ e- thyl)-3H-benzimidazo[2,l-b] ⁇ urin-4 ⁇ 5H)-one; 5,7,8,9-Tetrahydro-5-metl ⁇ yl-3-(phenylmethyl)- pyr cddop, l-b]purin- (3H)-one; 7,8-Dihydro-8-

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Abstract

L'invention porte sur un procédé de traitement des dysfonctions sexuelles, ce procédé consistant à administrer une quantité thérapeutiquement efficace d'une combinaison de phentolamine et d'un inhibiteur de la phosphodiestérase GPM (guanosine 3',5'-monophosphate) cyclique tel que sildenafil, ainsi que sur des compositions pharmaceutiques et les kits utilisés dans ces procédés.
PCT/US1999/007046 1998-05-20 1999-05-17 Combinaison de phentolamine et d'inhibiteurs de la phosphodiesterase gmp cyclique utilises dans le traitement des dysfonctions sexuelles WO1999059584A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40685/99A AU4068599A (en) 1998-05-20 1999-05-17 Combination of phentolamine and cyclic gmp phosphodiesterase inhibitors for the treatment of sexual dysfunction

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US8164098A 1998-05-20 1998-05-20
US09/081,640 1998-05-20
US8297798A 1998-05-21 1998-05-21
US09/082,977 1998-05-21
US10651798A 1998-06-29 1998-06-29
US09/106,517 1998-06-29

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US7923449B2 (en) 2005-10-29 2011-04-12 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
US8227476B2 (en) 2005-08-03 2012-07-24 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US8227471B2 (en) 2001-10-20 2012-07-24 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US8512748B2 (en) 2006-08-25 2013-08-20 Boehringer Ingelheim International Gmbh Controlled release system and method for manufacturing the same
US8658207B2 (en) 2006-08-14 2014-02-25 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053148A3 (fr) * 1999-03-08 2000-12-14 Merck & Co Inc Procedes et compositions pour le traitement de la dyserection
WO2000053148A2 (fr) * 1999-03-08 2000-09-14 Merck & Co., Inc. Procedes et compositions pour le traitement de la dyserection
NL1015027C2 (nl) * 1999-04-30 2001-02-14 Lilly Icos Llc Voortbrengsels.
GR20000100153A (el) * 1999-04-30 2000-12-29 Lilly Icos Llc Βιομηχανικα ειδη
FR2795646A1 (fr) * 1999-04-30 2001-01-05 Lilly Icos Llc Article manufacture pour un usage pharmaceutique humain
WO2000066099A3 (fr) * 1999-04-30 2001-01-18 Lilly Icos Llc Forme de dosage unitaire
BE1012957A5 (fr) * 1999-04-30 2001-06-05 Lilly Icos Llc Articles de fabrication.
ES2187234A1 (es) * 1999-04-30 2003-05-16 Lilly Icos Llc Forma de dosificacion oral para tratar la disfuncion sexual.
EP1415652A2 (fr) * 1999-04-30 2004-05-06 Lilly Icos LLC Composition comprenant des inhibiteurs de la phosphodiesterase pour traiter les disfonctionnements sexuels
EP1415652A3 (fr) * 1999-04-30 2004-05-12 Lilly Icos LLC Composition comprenant des inhibiteurs de la phosphodiesterase pour traiter les disfonctionnements sexuels
EA005416B1 (ru) * 1999-04-30 2005-02-24 ЛИЛЛИ АЙКОС эЛ-эЛ-Си Унифицированная дозированная лекарственная форма
US6943166B1 (en) 1999-04-30 2005-09-13 Lilly Icos Llc. Compositions comprising phosphodiesterase inhabitors for the treatment of sexual disfunction
WO2000066099A2 (fr) * 1999-04-30 2000-11-09 Lilly Icos Llc Forme de dosage unitaire
US7176311B2 (en) 1999-10-11 2007-02-13 Pfizer Inc. Process for preparing pharmaceutically active compounds
US6677335B1 (en) 1999-10-11 2004-01-13 Pfizer Inc Pharmaceutically active compounds
US7148350B2 (en) 2000-08-08 2006-12-12 Cristalia Prod.Qui.Farm. Ltda Compounds in the form of homodimeric or heterodimeric pro-drugs; process for obtaining these pro-drugs and their acceptable pharmaceutical salts and use of compounds in the treatment of phosphodiesterases-mediated diseases or dysfunction
US8227471B2 (en) 2001-10-20 2012-07-24 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US9782403B2 (en) 2001-10-20 2017-10-10 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US11058683B2 (en) 2001-10-20 2021-07-13 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US10874668B2 (en) 2005-08-03 2020-12-29 Sprout Pharmaceuticals, Inc. Use of Flibanserin in the treatment of obesity
US8227476B2 (en) 2005-08-03 2012-07-24 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US9730927B2 (en) 2005-08-03 2017-08-15 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US10335407B2 (en) 2005-08-03 2019-07-02 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US7923449B2 (en) 2005-10-29 2011-04-12 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US10004731B2 (en) 2006-06-30 2018-06-26 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US8658207B2 (en) 2006-08-14 2014-02-25 Boehringer Ingelheim International Gmbh Extended release tablet formulations of flibanserin and method for manufacturing the same
US8512748B2 (en) 2006-08-25 2013-08-20 Boehringer Ingelheim International Gmbh Controlled release system and method for manufacturing the same
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms

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