CN1233178A - Pyrazolinones to treat disturbances of potency - Google Patents

Pyrazolinones to treat disturbances of potency Download PDF

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Publication number
CN1233178A
CN1233178A CN97198764A CN97198764A CN1233178A CN 1233178 A CN1233178 A CN 1233178A CN 97198764 A CN97198764 A CN 97198764A CN 97198764 A CN97198764 A CN 97198764A CN 1233178 A CN1233178 A CN 1233178A
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Prior art keywords
methylene
dihydro
mea
oxo
pyrazol
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M·阿尔特
R·约纳斯
P·谢林
M·克里斯塔德勒
F·W·克卢克森
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Merck Patent GmbH
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Merck Patent GmbH
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    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The use of compounds having formula (I) wherein R<1>, R<2> and R<3> have the meanings given in claim 1, for the treatment and/or therapy of disturbances of potency.

Description

The pyrazoline ketone that is used for the treatment of sexual dysfunction
The present invention relates to use the chemical compound of formula I and its physiology to go up acceptable salt processing and/or therapeutic dysfunction,
R wherein 1Be not to be substituted or the mono-substituted benzyl of alkoxy, or be not substituted or by halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NH-CO-A, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A, tetrazole radical or PO 3H institute is single to be replaced, trisubstituted pyridine radicals of two replacements or phenyl,
R 2Be A, alkoxy-C O-alkylidene, HO-CO-alkylidene or HO-alkylidene,
R 3Be H, A, alkoxyl, NH2, NHA, NAA ', NH-CO-A or SO 2NR 4R 5,
R 4And R 5Be H or A independently of one another,
R 4And R 5Alternately be the alkylidene chain of a saturated or undersaturated wholly or in part 4-5 unit, wherein 1-3 carbon atom can be replaced by nitrogen-atoms and/or 1 or 2 carbon atom is replaced by 1 or 2 oxygen atom and/or 1 or 2 sulphur atom,
A and A ' be independently of one another for containing the alkyl of 1-6 carbon atom, wherein 1-7 hydrogen atom can by fluorine atom and/or the replacement of chlorine atom and
Halogen is fluorine, chlorine, bromine or iodine.
Pyrazoles-3-ketones derivant that DE19518082 has described, this paper asks for protection it according to the second medical indication.Therefore according to the indication of list of references, will in DE19518082, all incorporate the present invention into by disclosed full content.And this document discloses and has used these chemical compounds to be used to prepare a kind of medicine for the treatment of cardiovascular system diseases as the selective depressant of cGMP specific phosphodiesterase enzyme.
We find that surprisingly the chemical compound of indication of the present invention can be used in processing and/or therapeutic dysfunction (erection disturbance).
Use pyrazoline-substituting ketone Pyrimdinone to handle the existing description of sexual impotence, for example in WO94/28902.
The biological activity of the chemical compound of formula I can be determined with the method for for example describing in WO93/06104.Noval chemical compound to the affinity of cGMP and cAMP phosphodiesterase by by measuring their IC 50Value (inhibitory enzyme activity about 50% required inhibitor concentration) is determined.
The available enzyme that is separated to by known method (for example: W.J.Thompson etc., " biochemistry " 1971,10,311) is measured.Test can adopt a kind of improved " batch " method (" biochemistry " 1979,18,5228) of W.J.Thompson and M.M.Appleman to carry out.
These chemical compounds are effective especially as the inhibitor of the specimen cavernous body of penis contracture of the inductive hare of phenylephrine.
This effect can be passed through, and for example, F.Holmquist etc. are at " urology magazine " 150, and the method for describing among the 1310-1315 (1993) obtains proof.
Suppress contracture, show that these noval chemical compounds can effectively handle and/or the therapeutic dysfunction, this by the representation compound of some formula I through experiment confirm.The pharmacology data of experiment is listed in the table I.
The chemical compound of formula I can be used as the effective ingredient in medicine and the veterinary drug.
A and A ' are independently of one another, preferably have the alkyl of 1-6 carbon atom.
In above-mentioned general formula, alkyl is preferably unbranched and contain 1,2,3,4,5 or 6 carbon atom, preferably contain 1,2,3,4 or 5 carbon atom, preferably methyl, ethyl or propyl group, and not only isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, n-pentyl, neopentyl or isopentyl also are preferred.
In addition, preferably trifluoromethyl or penta fluoro ethyl of A.
Alkylidene is preferably unbranched and be methylene, vinyl, acrylic, cyclobutenyl or pentenyl.
Alkoxyl is preferably methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy or hexyloxy.
R 4And R 5Jointly preferably-CH 2-CH 2-CH 2-CH 2-,-CH 2-(CH 2) 3-CH 2,-CH 2-CH 2-O-CH 2-CH 2-,-CH 2-CH 2-NH-CH 2-CH 2-,-CH 2-CH 2-NA-CH 2-CH 2-,-CH 2-O-CH 2-CH 2-or-CH=CHCH=CH-.
Halogen is fluorine, chlorine or bromine preferably, and iodine also is preferred.
For whole invention, the fact is that the group that is occurred more than once can be identical or different, that is to say, is mutually independently.
The present invention relates to use the chemical compound with formula I more precisely, and wherein at least a above-mentioned group has one of above-mentioned preferred meaning.Some preferred chemical compound groups can represent to I d with following secondary formula I a, and they are all corresponding to formula I, and do not have the definition in more detailed specified group such as the formula I in secondary general formula, but wherein in I a, R 1Be not to be substituted or the mono-substituted benzyl of alkoxy, or be not substituted or coverlet replacement, two replacement or trisubstituted pyridine radicals or phenyl that its substituent group is halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NH-CO-A, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A or tetrazole radical
R 2Be A, alkoxy-C O-alkylidene or HO-alkylidene,
R 3Be A or alkoxyl,
R 4And R 5Be H or A independently of one another,
R 4And R 5Alternately be the alkylidene chain of saturated or unsaturated fully or the undersaturated 4-5 of a part unit, wherein 1-3 carbon atom can be replaced by nitrogen-atoms and/or 1 or 2 carbon atom by 1 or 2 oxygen atom and/or 1 or 2 sulphur atom replacement
A and A ' be independently of one another for containing the alkyl of 1-6 carbon atom, wherein 1-7 hydrogen atom can by fluorine atom and/or the replacement of chlorine atom and
Halogen is fluorine, chlorine, bromine or iodine.In I b, R 1Be not to be substituted or benzyl that alkoxy replaces, or be not substituted or coverlet replaces, two replacement or trisubstituted pyridine radicals or phenyl that its substituent group is halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NH-CO-A, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A or tetrazole radical R 2Be A, alkoxy-C O-alkylidene, the HO-alkylidene,
R 3Be A or alkoxyl,
R 4And R 5Be H or A independently of one another, A and A ' be independently of one another for containing the alkyl of 1-6 carbon atom, wherein 1-7 hydrogen atom can by fluorine atom and/or the replacement of chlorine atom and
Halogen is fluorine, chlorine, bromine or iodine.In I c, R 1Be not to be substituted or benzyl that alkoxy replaces, or be not substituted or coverlet replaces, two replacement or trisubstituted pyridine radicals or phenyl that its substituent group is halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NH-CO-A, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A or tetrazole radical
R 2Be A, alkoxy-C O-alkylidene, or HO-alkylidene,
R 3Be A or alkoxyl,
R 4And R 5Alternately be the alkylidene chain of saturated or unsaturated fully or the undersaturated 4-5 of a part unit, wherein 1-3 carbon atom can be replaced by nitrogen-atoms and/or 1 or 2 carbon atom by 1 or 2 oxygen atom and/or 1 or 2 sulphur atom replacement
A and A ' be independently of one another for containing the alkyl of 1-6 carbon atom, wherein 1-7 hydrogen atom can by fluorine atom and/or the replacement of chlorine atom and
Halogen is fluorine, chlorine, bromine or iodine.In I d, R 1Be not to be substituted or benzyl that alkoxy replaces, or not coverlet replace, two replacement or trisubstituted pyridine radicals or phenyl, its substituent group is halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NH-CO-A, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A or tetrazole radical,
R 2Be A, alkoxy-C O-alkylidene, or HO-alkylidene,
R 3Be A or alkoxyl,
R 4And R 5Be H or A independently of one another,
R 4And R 5Alternately be-CH 2-CH 2-CH 2-CH 2-,-CH 2-(CH 2) 3-CH 2,-CH 2-CH 2-O-CH 2-CH 2-,
-CH 2-CH 2-NH 2-CH 2-CH 2-,-CH 2-CH 2-NA-CH 2-CH 2-,-CH 2-O-CH 2-CH 2-or
-CH=CHCH=CH-。
A and A ' be independently of one another for containing the alkyl of 1-6 carbon atom, wherein 1-7 hydrogen atom can by fluorine atom and/or the replacement of chlorine atom and
Halogen is fluorine, chlorine, bromine or iodine.
The particularly preferred following compounds that is to use:
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) benzoic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) benzoic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) Benzoylamide
N-(4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) acetamide
2-(1-(4-methoxycarbonyl aminophenyl)-4-(2-MEA methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
2-(4-(2-MEA methylene)-4,5-dihydro-1-(4-methyl sulfonamido phenyl)-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
2-(4-(2-MEA methylene)-4,5-dihydro-1-(4-(N, N-diethyl sulfonamido) phenyl)-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester.
N-(4-(4-(2-MEA methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl) phenyl)-N-methyl-sulfonamide
2-(1-(4-(N, N-diethyl amino sulphonyl) phenyl)-4-(2-MEA methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
4-[(2-methoxyphenyl amino) methylene]-2,4-dihydro-5-methyl-2-Phenylpyrazole-3-ketone
4-[(2-propoxyl group phenyl amino) methylene]-2,4-dihydro-5-methyl-2-Phenylpyrazole-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(4-methoxybenzyl) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-(2-ethoxy)-2-Phenylpyrazole-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(4-bromobenzene) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(4-Nitrobenzol) pyrazoles-3-ketone
3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) benzenesulfonic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) benzenesulfonic acid
4-(2-MEA methylene)-2,4-dihydro-5-methyl-2-(4-Nitrobenzol) pyrazoles-3-ketone
2-(4-(2-MEA methylene)-4,5-dihydro-1-(4-Nitrobenzol)-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(2-pyridine radicals) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-methyl-2-(2-pyridine radicals) pyrazoles-3-ketone
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N-hexyl benzene Methanamide
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N, N-diethylbenzene Methanamide
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(4-pyridine radicals) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-methyl-2-(4-chlorphenyl) pyrazoles-3-ketone
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl)-N, N-diethylbenzene Methanamide
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl)-N-hexyl benzene Methanamide
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) Benzoylamide
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) phenylcyanide
3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl)-N, N-diethyl-4-methoxy benzsulfamide
3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenylcyanide
4-(2-MEA methylene)-2,4-dihydro-5-methyl-2-(4-(4-morpholine sulfonyl) phenyl) pyrazoles-3-ketone
3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl methyl)-N-hexyl-4-propoxyl group-benzsulfamide
3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) benzoic acid
N-(3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) acetamide
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N, the N-diethyl benzene sulfonamide
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(4-(1H-tetrazolium-5-yl) phenyl) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-propyl group-2-(3-pyridine radicals) pyrazoles-3-ketone
4-(2-MEA methylene)-2,4-dihydro-5-methyl-2-(3-(1H-tetrazolium-5-yl) phenyl) pyrazoles-3-ketone
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N-ethylo benzene sulfonamide
4-(2-butoxy base anilino-methylene)-2,4-dihydro-5-methyl-2-(4-(4-morpholine sulphonyl) phenyl) pyrazoles-3-ketone
4-(2-ethyoxyl base anilino-methylene)-2,4-dihydro-5-methyl-2-(4-(4-morpholine sulphonyl) phenyl) pyrazoles-3-ketone
4-(2-ethyl base anilino-methylene)-2,4-dihydro-5-methyl-2-(4-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl) pyrazoles-3-ketone
N-(3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) amsacrine
N-(3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) carbamic acid methyl ester
N-(2-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) amsacrine
N-(3-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) three fluoro acetamides
4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N, the N-diethyl benzene sulfonamide
4-(4-(2-aminoanisole methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N, the N-diethyl benzene sulfonamide
4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N-ethylo benzene sulfonamide
N-(4-(4-(2-aminoanisole methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) carbamic acid ethyl ester
4-(4-(2-trifluoro acute pyogenic infection of nails base anilino-methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-benzoic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-ethoxy carbonyl methyl isophthalic acid H-pyrazol-1-yl) benzoic acid
4-(4-(2-propoxyl group anilino-methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-benzoic acid
N-(4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) propionic acid amide.
4-(4-(2-aminoanisole methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) benzoic acid
4-(4-(2-isopropyl aniline methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) benzoic acid
4-(4-(2-phenetidine methylene)-2,4 dihydros-5-methyl-2-(4-(1-piperdine sulfonyl) phenyl) pyrazoles-3-ketone
4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N-tert-butyl benzene sulfonamide
4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl)-N-acetylbenzene sulfonamide
4-(4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) benzsulfamide
2-(1-(4-N, N-diethyl amino sulfonyl) phenyl)-4-(2-phenetidine methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) the acetic acid ethyl ester
2-(1-(4-acetamido phenyl)-4-(2-MEA methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
2-(1-(4-three fluoro acetamido phenyl)-4-(2-MEA methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
The invention still further relates to and use chemical compound and/or the last acceptable salt of its physiology to come useful in preparing drug formulations, particularly pass through method non-chemically with formula I.In this scope, they can make a kind of suitable dosage form with at least a solid, liquid and/or semiliquid excipient or auxiliary agent, as needs, can add one or more other active component.
The invention still further relates to and use chemical compound with formula I and/or its physiology to go up acceptable salt to prepare and be used for handling and/or the handicapped medicine of therapeutic.
The present invention relate in addition be used for handling and or the handicapped pharmaceutical preparation of therapeutic, it contains at least a chemical compound and/or its a kind of physiology with formula I and goes up acceptable salt.
The invention still further relates to that use can be handled and/or the handicapped pharmaceutical preparation of therapeutic, it comprises at least a chemical compound and/or its at least a physiology with formula I and goes up acceptable salt.
These preparations can be as drug use in human medicine or veterinary drug.Suitable excipient is to be applicable to outside enteral (as: mouth), the intestinal or the Organic substance or the inorganic matter of topical application, they do not react with noval chemical compound, for example water, vegetable oil, benzyl alcohol, ethylene glycol, Polyethylene Glycol, glyceryl triacetate, gelatin, carbohydrate such as lactose or starch, magnesium stearate, Pulvis Talci and vaseline.In order to orally use, make tablet, pill, sugar coated tablet, capsule, powder, granule, syrup, juice or drop especially; Be used for rectally, make suppository; Be used for the intestinal external administration, make solution, preferably oiliness or aqueous solution, suspension, Emulsion or graft also are preferred; Be used for local the use, make ointment, emulsifiable paste or powder.But noval chemical compound is lyophilizing also, and the lyophozyme of formation can be used for preparation, for example, and ejection preparation.Preparation described above can be sterilized and/or can be comprised auxiliary agent, for example other effective ingredient of fluidizer, antiseptic, stabilizing agent and/or wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer agent, coloring agent, taste corrigent and/or some, for example one or more vitamin.
Have the chemical compound of formula I and their physiology and go up acceptable salt and can be used for resist the disease, show as cGMP (ring guanosine list phosphoric acid) thus level raises and causes suppressing or prevent inflammation and disease of flaccid muscles.Noval chemical compound especially can be used for treating the disease of cardiovascular system and is used for handling and the therapeutic dysfunction.
In these indications, usually preferred dosage is between every dosage unit about 1 to 500mg, particularly preferably is between 5 to 100mg.Daily dose is preferably in about 0.02 to 10mg/Kg body weight.Yet each patient's concrete dosage depends on multiple factor, for example the order of severity of the combination of the effect of the particular compound of Cai Yonging, age, body weight, health status at ordinary times, sex, meals, time of administration and approach, excretory speed, medicine and the various diseases for the treatment of.Oral is preferred.
The synthetic method of these chemical compounds has been described at DE195 18 082.What at this on the one hand, list of references was described is about drug regimen above-mentioned.The principle of preparation does not just repeat herein.Embodiment 1
The following table I has been listed some typical compounds with formula I and has been suppressed the result of the test that phenylephrine is induced the cloudy basic Sponge specimen contracture of hares.For relaxation test, listed IC 50Value, just in μ mol/L, suppress the concentration of 50% the inductive spasm of phenylephrine (contracture).The table I
By with F.Holmquist etc. at " urology magazine ", 150, the similar IC of the typical compound that obtains of method among the 1310-1315 (1993) with formula I 50Value (concentration is in μ mol/L), and the mensuration fusing point of these materials.
R 1 ?R 2 ?R 3 ?m.p.[℃] IC 50
(1) Me ?2-Et ?287-291 ?0.2
(1) Pr ?2-Et ?255 ?0.1
(2) Me ?2-Et ?225 ?0.6
(3) Me ?2-Et ?230 ?2.0
(4) CH 2COOEt ?2-Et ?145 ?0.1
(5) CH 2COOEt ?2-Et ?165 ?0.2
(6) CH 2COOEt ?2-Et ?1.0
Figure A9719876400132
Me=methyl Et=ethyl Pr=propyl group
Pharmacology data has proved inhibition activity and their treatments of the chemical compound with formula I and/or has handled the effectiveness of sexual dysfunction.Following Example relates to pharmaceutical preparation: embodiment A: injection bottle
A kind of effective ingredient and the 5g sodium hydrogen phosphate of 100g formula I are dissolved in the 3L double distilled water, obtain a kind of solution and regulate pH value to 6.5 with 2N hydrochloric acid, carry out aseptic filtration then, the injection bottle of packing into, lyophilizing and sterile sealing under aseptic condition.Every injection bottle contains the 5mg effective ingredient.Example B: suppository
A kind of effective ingredient of 20g formula I, 100g soybean lecithin and 1400g cocoa ester mix, and mold is poured in fusing into, waits its cooling again.Every suppository contains the 20mg effective ingredient.Embodiment C: solution
A kind of effective ingredient of 1g formula I and 9.38g NaH 2PO 42H 2O, 28.48gNa 2HPO 412H 2O, the 0.1g geramine is dissolved in the 940ml double distilled water.Solution is regulated pH to 6.8, and volume is to 1L, and sterilizes with radioactive method.This solution can be used as collyrium.Embodiment D: ointment
A kind of effective ingredient of 500mg formula I mixes under aseptic condition with 99.5g vaseline.Embodiment E: tablet
The effective ingredient of 1kg formula I and 4kg lactose, the 1.2kg potato starch, 0.2kg Pulvis Talci and 0.1kg magnesium stearate are mixed, and are pressed into tablet according to customary way, and every contains the 10mg effective ingredient.Embodiment F: sugar coated tablet
According to the similar method compressed tablets of embodiment E, use customary way sucrose then, potato starch, Pulvis Talci, the coating of tragacanth and coloring agent is coated on the tablet.Embodiment G: capsule
The effective ingredient of 2kg formula I is by the customary way hard gelatine capsule of packing into.Every capsule contains the 20mg effective ingredient.Example H: ampulla
The effective ingredient of 1kg formula I is dissolved in the 60L double distilled water, aseptic filtration then, and the ampoule of packing into+, lyophilizing and sterile sealing under aseptic condition.Every ampoule+contain 10mg effective ingredient.Embodiment I: suck spray
The effective ingredient of 14g formula I is dissolved in the isoosmotic NaCl solution of 10L, the automiser spray of the habitual commercial band pump of packing into then.This solution can spray into face and nose.Discharge rate once (approximately 0.1ml) is equivalent to the dosage of about 0.14mg.

Claims (6)

1. one kind is used the chemical compound of formula I and its physiology to go up acceptable salt processing and/or the handicapped purposes of therapeutic,
Figure A9719876400021
R wherein 1Be not to be substituted or benzyl that alkoxy replaces, or be not substituted or coverlet replaces, two replacement or trisubstituted pyridine radicals or phenyl that its substituent group is halogen, NO 2, CN, COOH, CONH 2, CONHA, CONAA ', NH 2, NH-CO-A, NH-SO 2A, SO 2NH-CO-A, NA-SO 2A ', NH-CO-OA, SO 3H, SO 2NR 4R 5, CO-NHSO 3H, CO-NHSO 2A, tetrazole radical or PO 3H,
R 2Be A, alkoxy-C O-alkylidene, HO-CO-alkylidene or HO-alkylidene,
R 3Be H, A, alkoxyl, NH2, NHA, NAA ', NH-CO-A or SO 2NR 4R 5,
R 4And R 5Be H or A independently of one another,
R 4And R 5Alternately be the alkylidene chain of saturated or unsaturated fully or the undersaturated 4-5 of a part unit, wherein 1-3 carbon atom can be replaced by nitrogen-atoms and/or 1 or 2 carbon atom by 1 or 2 oxygen atom and/or 1 or 2 sulphur atom replacement
A and A ' are independently of one another for containing the alkyl of 1-6 carbon atom, and wherein 1-7 hydrogen atom can be replaced by fluorine atom and/or chlorine atom, and
Halogen is fluorine, chlorine, bromine or iodine.
2. one kind is used a kind of processing of compound of formula I as claimed in claim 1 and/or the purposes of the handicapped medicine of therapeutic.
3. a use is selected from the compound treatment and/or the handicapped purposes of therapeutic of following formula I as claimed in claim 1:
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) benzoic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-propyl group-1H-pyrazol-1-yl) benzoic acid
4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) Benzoylamide
N-(4-(4-(2-MEA methylene)-4,5-dihydro-5-oxo-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl) acetamide
2-(1-(4-methoxycarbonyl aminophenyl)-4-(2-MEA methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
2-(4-(2-MEA methylene)-4,5-dihydro-1-(4-methyl sulfonamido phenyl)-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester
2-(4-(2-MEA methylene)-4,5-dihydro-1-(4-(N, N-diethyl sulfonamido) phenyl)-5-oxo-1H-pyrazole-3-yl) acetic acid ethyl ester.
4. one kind prepares and is used to handle and/or the method for the handicapped pharmaceutical preparation of therapeutic, it is characterized in that the chemical compound of formula I as claimed in claim 1 and/or its a kind of physiology go up acceptable salt and be prepared into a kind of suitable dosage form with at least a solid, liquid or semiliquid excipient or auxiliary agent.
5. one kind is used for handling and/or the handicapped pharmaceutical preparation of therapeutic, it is characterized in that chemical compound and/or its a kind of physiology of containing at least a formula I as claimed in claim 1 go up acceptable salt.
6. a use contains the chemical compound of at least a formula I as claimed in claim 1 and/or pharmaceutical preparation processing and/or the handicapped purposes of therapeutic that its at least a physiology goes up acceptable salt.
CN97198764A 1996-10-14 1997-10-08 Pyrazolinones to treat disturbances of potency Pending CN1233178A (en)

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DE19642284A DE19642284A1 (en) 1996-10-14 1996-10-14 Pyrazolinones for the treatment of erectile dysfunction

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US6410584B1 (en) 1998-01-14 2002-06-25 Cell Pathways, Inc. Method for inhibiting neoplastic cells with indole derivatives
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6486155B1 (en) 1998-11-24 2002-11-26 Cell Pathways Inc Method of inhibiting neoplastic cells with isoquinoline derivatives
US6875575B1 (en) 1998-11-25 2005-04-05 Osi Pharmaceuticals, Inc. Diagnostic methods for neoplasia
US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia

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