HK1114083A - Thienopyridinone compounds and methods of treatment - Google Patents

Description

Thienopyridinone compounds and methods of treatment

Technical Field

The present invention relates generally to 5-hydroxytryptamine (5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., 5-HT₄Agonists, partial agonists, inverse agonists and antagonists, and more particularly to novel thienopyridinone compounds, the synthesis and use of these compounds and their pharmaceutical compositions, e.g. for the treatment, modulation and/or prevention of physiological conditions associated with 5-hydroxytryptamine effects, e.g. for the treatment of alzheimer's disease, cognitive disorders, irritable bowel syndrome, nausea, vomiting (emesis), emesis (voicing), prokinesis, gastroesophageal reflux disease and non-ulcer dyspepsia.

Background

It has been shown that the 5-hydroxytryptamine-capable nervous system of the brain affects a variety of physiological functions which manifest themselves in a variety of disorders, such as alzheimer's disease, cognitive disorders, irritable bowel syndrome; nausea, vomiting, prokinesis, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorder, eating disorder, gastrointestinal disorder, constipation, erectile dysfunction, and respiratory depression.

5-HT receptor modulators, e.g., agonists, partial agonists, inverse agonists and antagonists and/or selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, fluvoxamine, sertraline, clohydroxydesmopram, imipramine, citalopram and nortriptyline, are useful in the treatment of the above conditions, as well as in vasodilation, smooth muscle contraction, bronchoconstriction, brain disorders such as vascular conditions such as angina and migraine, and neuropathological disorders including Parkinson's disease and Alzheimer's disease. They also intervene in the regulation of the cerebral circulation and therefore represent effective agents for controlling migraine. They are also suitable for preventing and controlling the occurrence of cerebral infarctions (cerebral stroke), such as the effects of stroke or cerebral ischemia. They are also suitable for controlling intestinal disorders which are characterized by a disturbance of the 5-hydroxytryptamine energy system and also by a disturbance of the sugar metabolism. They are suitable for the treatment of gastrointestinal disorders, including irritable bowel syndrome.

Tegaserod, a salt thereof as 5-HT₄The indazole carbazimidamide, which acts as an agonist, has been approved for irritable bowel syndrome. (Buchheit et al J.Med.chem.1995, 38, 2331-.

5-HT₄The receptor represents one member of a family of receptors with 7 transmembrane (7TM) domains coupled to G-proteins that are positively coupled to adenylate cyclase. 5-HT₄Receptors are expressed in a variety of tissues, including human and rodent brain, human, dog, porcine and rodent gastrointestinal tract, and porcine and human heart. In the mammalian brain, 5-HT₄Receptors promote dopamine secretion, and regulate learning and long-term memory by altering acetylcholine release. In peripheral tissues, 5-HT has been demonstrated₄The receptors modulate gastrointestinal motility, intestinal electrolyte secretion, adrenal secretion of corticosteroids, bladder contraction and atrial contractionAnd (4) sex.

5-HT₄Receptors are involved in a wide variety of central and peripheral disorders, including cardiac arrhythmias and neurodegenerative disorders, more specifically alzheimer's disease, cognitive disorders, irritable bowel syndrome, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction and respiratory depression.

5-HT₄The development of receptor modulators, such as agonists, partial agonists, inverse agonists and antagonists, may have therapeutic applications in the central nervous system for the treatment of neuropsychiatric disorders associated with dysfunction of the central dopaminergic system, such as parkinson's disease, or for the treatment of amnesic deficiencies as present in patients suffering from alzheimer's disease. These drugs may also be used to treat peripheral disorders such as irritable bowel syndrome, gastroparesis, urinary incontinence and cardiac arrhythmias. Selective, high affinity, metabolically stable 5-HT with good bioavailability, CNS penetration and good pharmacokinetic properties (e.g. in vivo)₄Receptor modulators are desirable.

Summary of The Invention

The present invention relates to the discovery that a novel compound is 5-HT₄Modulators, such as agonists, partial agonists, inverse agonists and antagonists, may be useful for the treatment, prevention or cure of 5-HT associated conditions, such as Alzheimer's disease, cognitive disorders, irritable bowel syndrome, Parkinson's disease, gastroparesis, urinary incontinence and cardiac arrhythmias.

In particular, it has now been found that certain thienopyridinone compounds are effective 5-HT₄Receptor partial agonists and/or full agonists and act as antagonists and/or SSRIs. In one embodiment, such compounds include those having the formulaCompounds, and pharmaceutically acceptable salts and/or esters thereof:

wherein

R₁May be ethyl or isopropyl; and R is₂Optionally substituted alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, methylcyclopropyl, isopropyl alcohol, phenethyl.

The compounds of the present invention also include those having the formula

Wherein

R₁Can be (C)₁-C₈) A branched or unbranched alkyl or alkenyl group; (C)₁-C₈) A substituted or unsubstituted carbocyclic ring; a substituted or unsubstituted aryl or heteroaryl ring; with branched or unbranched haloalkyl groups (e.g. CF)₃、CF₃-CH₂、CF₃-CF₂-) according to the formula (I); or substituted or unsubstituted (CH)₂)_p-aryl or (CH)₂)_p-a heteroaryl ring, wherein p is 1, 2, 3 or 4; and is

R₂May be optionally substituted (C)₁-C₆) With branched or unbranched alkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy or alkanoyl groups. R₂Suitable substituents above include substituted or unsubstituted aryl; a hydroxyl group; (C)₁-C₆) A substituted or unsubstituted carbocyclic ring; substituted or unsubstituted (C)₁-C₆) Alkylhydroxy, substituted or unsubstituted (C)₁-C₆) Alkylalkoxy, substituted or unsubstituted (C)₁-C₆) Alkylamino, substitutedOr unsubstituted (C)₁-C₆) Alkylaminoacyl, substituted or unsubstituted (C)₁-C₆) An alkylamino aryl group.

Suitable R₂The groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl.

The compounds of the present invention may also be 5-HT receptor modulators, such as 5-HT₄Receptor agonists, partial agonists, inverse agonists and/or antagonists.

In another embodiment, the compounds of the invention may also be 5-HT receptor agonists, e.g., 5-HT₄A receptor agonist.

In another embodiment, the compounds of the invention may also be partial agonists of 5-HT receptors, such as 5-HT₄A receptor partial agonist.

In another embodiment, the compounds of the invention may also be 5-HT receptor inverse agonists, such as 5-HT₄Receptor inverse agonists.

In another embodiment, the compounds of the invention may also be 5-HT receptor antagonists, such as 5-HT₄A receptor antagonist.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula I or II in an amount effective to treat a disorder, such as alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, prokinesis, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, eating disorders, gastrointestinal disorders, constipation, erectile disorders, or respiratory depression, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating a disease in a mammal, such as a human, which comprises administering a therapeutically effective amount of a compound of formula I or II, such as alzheimer's disease, a cognitive disorder, irritable bowel syndrome, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile disorders, or respiratory depression.

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula I or II effective to treat alzheimer's disease in a mammal suffering from the disease and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating Alzheimer's disease in a mammal, such as a human, which comprises administering a therapeutically effective amount of a compound of formula I or II.

Another aspect of the invention is a pharmaceutical composition comprising a memory enhancing effective amount of a compound of formula I or II and a pharmaceutically acceptable carrier for enhancing memory in a mammal in need of memory enhancement.

Another aspect of the invention is a method for memory enhancement in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula I or II.

Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound of formula I or II for treating Irritable Bowel Syndrome (IBS) and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating Irritable Bowel Syndrome (IBS) comprising administering a therapeutically effective amount of a compound of formula I or II.

Also included in the invention are methods of making the compounds and novel intermediates.

Detailed Description

Features and other details of the present invention will now be described more particularly with reference to the accompanying drawings and pointed out in the claims. It will be understood that the particular embodiments described herein are shown by way of illustration and not as limitations on the scope of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise indicated.

Definition of

For convenience, certain terms used in the specification, examples, and claims are collected here.

"5-HT receptor modulators" or "5-HT modulators" include compounds that have an effect on: 5-HT₁、5-HT₂、5-HT₃、5-HT₄、5-HT₅、5-HT₆Or 5-HT₇Receptors, including subtypes of each type of receptor, e.g. 5-HT_{1A, B, C, D, E or F}；5-HT_{2A, B or C}；h5-HT_{4a, b, c, d or e}(ii) a And 5-HT_{5A or B}. The 5-HT modulator may be an agonist, a partial agonist, an inverse agonist or an antagonist.

"treating" includes any effect, such as alleviation, reduction, modulation, or elimination, that results in amelioration of the condition, disease, disorder, or the like.

"alkyl" includes saturated aliphatic groups, including straight-chain alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkyl (e.g., isopropyl, t-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. "alkyl" further includes alkyl groups having oxygen, nitrogen, sulfur or phosphorous atoms in place of one or more hydrocarbon backbone carbon atoms. In certain embodiments, a straight or branched chain alkyl group has six or fewer carbon atoms in its backbone (e.g., straight chain C)₁-C₆Branched chain C₃-C₆) And more preferably four or less. Likewise, cycloalkyl groups preferably have 3 to 8 carbon atoms in their ring structure, more preferably 5 or 6 carbons in the ring structure. "C₁-C₆"includes containing 1 toAlkyl of 6 carbon atoms.

The term "alkyl" also includes "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyl groups may be further substituted, for example, with the substituents described above. An "alkylaryl" or "arylalkyl" moiety is an alkyl group substituted with an aryl group (e.g., phenylmethyl (phenylmethyl)). "alkyl" also includes the side chains of natural and unnatural amino acids.

"aryl" includes aromatic groups, including 5-and 6-membered "nonconjugated", or monocyclic, aromatic groups which may include 0-4 heteroatoms, and "conjugated", or polycyclic, systems having at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Furthermore, the term "aryl" includes polycyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups that have heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heteroaryls" or "heteroaromatics". The aromatic ring may be substituted at one or more ring positions with such substituents as described above, as halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The aryl group may also be fused or bridged with aliphatic or heterocyclic rings which are not aromatic so as to form a polycyclic ring system (e.g., tetrahydronaphthalene, methylenedioxyphenyl).

"alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but which includes at least one double bond. For example, the term "alkenyl" includes a straight alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched alkenyl, cyclic alkenyl (e.g., alicyclic) group (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl-or alkenyl-substituted cycloalkenyl, and cycloalkyl-or cycloalkenyl-substituted alkenyl. The term "alkenyl" further includes alkenyl groups containing oxygen, nitrogen, sulfur or phosphorous atoms in place of one or more hydrocarbon backbone carbons. In some embodiments, a straight or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., straight chain C)₂-C₆Branched chain C₃-C₆). In the same way as above, the first and second,cycloalkenyl groups can have 3 to 8 carbon atoms in their ring structure, more preferably 5 or 6 carbons in the ring structure. The term "C₂-C₆"includes alkenyl groups containing 2 to 6 carbon atoms.

The term "alkenyl" also includes "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. These substituents can include, for example, alkyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

"alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched chain alkynyl groups, and cycloalkyl-or cycloalkenyl-substituted alkynyl groups. The term "alkynyl" further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In some embodiments, a straight or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., straight chain C)₂-C₆C of a branched chain₃-C₆). The term "C₂-C₆"includes alkynyl groups containing 2 to 6 carbon atoms.

The term "alkynyl" can also include "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. These substituents may include, for example, alkyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, "lower alkyl" includes alkyl groups as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its backbone structure. "lower alkenyl" and "lower alkynyl" have a chain length of, for example, 2 to 5 carbon atoms.

"acyl" includes acyl (CH)₃CO-) or carbonyl groups. "substituted acyl" includes acyl in which one or more hydrogen atoms are replaced by a substituent such as alkyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, and the likeAn alkylsulfinyl, sulfonate, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

"amido" includes moieties in which an acyl moiety is attached to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

"alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups as described above, which further include oxygen, nitrogen or sulfur atoms, such as oxygen, nitrogen, or sulfur atoms, in place of one or more of the hydrocarbon backbone carbon atoms.

The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, propoxy, butoxy and pentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido); amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

The term "heterocyclyl" or "heterocyclic group" includes closed ring structures, e.g., 3-to 10-, or 4-to 7-membered rings, which include one or more heteroatoms. Heterocyclyl groups may be saturated or unsaturated and include pyrrolidine, oxolane, thiacyclopentane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinone and pyrrolidone, sultams, sultones, and the like. One or more positions of the heterocyclic ring may be substituted with the above-mentioned substituents, for example, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonate, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety.

The term "thiocarbonyl" or "thiocarboxyl" includes compounds and moieties containing a carbon with a double bond to the sulfur atom.

The term "ether" includes compounds or moieties that contain an oxygen attached to two different carbon or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom, which in turn is covalently bonded to another alkyl group.

The term "ester" includes compounds and moieties that contain a carbon or heteroatom attached to an oxygen atom that is attached to a carbon of a carbonyl group. The term "ester" includes alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and the like. Alkyl, alkenyl, or alkynyl groups are as defined above.

The term "thioether" includes compounds and moieties that contain a sulfur atom attached to two different carbons or heteroatoms. Examples of thioethers include, but are not limited to, alkylthioalkyl, alkylthioalkenyl, and alkylthioalkynyl. The term "alkylthioalkyl" includes compounds in which an alkyl, alkenyl, or alkynyl group is attached to a sulfur atom which is attached to an alkyl group. Similarly, the terms "alkylthioalkenyl" and "alkylthioalkynyl" refer to compounds or moieties in which an alkyl, alkenyl, or alkynyl group is attached to a sulfur atom, which is covalently attached to the alkynyl group.

The term "hydroxy" or "hydroxy" includes a compound having-OH or-O^-A group of (1).

The term "halogen" includes fluorine, bromine, chlorine, iodine, and the like. The term "perhalogenated" generally refers to a moiety in which all hydrogen atoms are replaced with halogen atoms.

"heteroatom" includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.

It is noted that some compounds of the present invention have structures that include asymmetric carbon atoms. It is therefore to be understood that isomers resulting from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the present invention unless otherwise indicated. These isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. In addition, the structures, other compounds and moieties discussed in this application also include all tautomers thereof. The olefin may also include E-or Z-geometry, if desired.

"combination therapy" (or "co-therapy") includes the administration of a 5-HT modulator of the present invention and at least one second agent as part of a particular treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action of the combination of therapeutic agents. Administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually minutes, hours, days or weeks, depending on the combination chosen). "combination therapy" can, but generally is not intended to, encompass the administration of two or more of these therapeutic agents as part of a single treatment regimen, which concomitantly and arbitrarily results in the combination of the present invention. "combination therapy" is intended to include the administration of these therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of them, in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule or multiple, single capsules of each therapeutic agent in a fixed ratio. Sequential or substantially simultaneous administration of each therapeutic agent may be achieved by any suitable route, including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent in a selected combination may be administered by intravenous injection, while another therapeutic agent in the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The order of administration of the therapeutic agents is not strictly critical. "combination therapy" may also include the administration of the above therapeutic agents in further combination with other bioactive ingredients and non-drug therapies such as surgery or radiation therapy. When the combination therapy further includes a non-drug therapy, the non-drug therapy can be administered at any suitable time so long as the beneficial effect is achieved by the combined action of the therapeutic agent and the non-drug therapy. For example, where appropriate, beneficial effects may still be obtained when non-drug therapy is temporarily withdrawn from administration of the therapeutic agent (perhaps several days or even weeks).

As used herein, "anionic group" refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate or thiophosphate or functional equivalents thereof. "functional equivalents" of anionic groups are intended to include bioisosteres, such as carboxylate groups. Bioisosteres include classical bioisosteres equivalents and non-classical bioisosteres equivalents. Classical and non-classical bioisosteres are well known in the art (see, e.g., Silverman, R.B. the Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp.19-23). Particularly preferred anionic groups are carboxylates.

The term "heterocyclyl" is intended to include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen, oxygen, or sulfur. Heterocyclic groups may be saturated or unsaturated, and heterocyclic groups such as pyrrole and furan have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. One or more of the constituent atoms of the heterocyclic group may also be replaced by, for example, halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxy, -CF₃-CN, etc.

The compounds of the invention are generally useful for the treatment or prevention of gastrointestinal disorders, cardiovascular disorders and CNS disorders. They have the potential benefit of treating Irritable Bowel Syndrome (IBS), especially diarrhea in IBS, of preventing the ability of 5-HT to stimulate bowel movement by activating gut neurons. In animal models of IBS, this can be conveniently measured in terms of a slowing of defecation speed. They may also be useful in the treatment of urinary incontinence commonly associated with IBS. They may also be useful in the treatment of other gastrointestinal disorders, such as those associated with upper bowel movement, and as anti-emetics. In particular, they may be used to treat gastroesophageal reflux disease and dyspepsia, nausea and gastric symptoms. Antiemetic activity is measured in a known animal model of cytotoxic agent/radiation induced emesis.

It would also be expected that certain cardiac 5-HT will prevent atrial fibrillation and other 5-HT associated atrial arrhythmias₄Receptor antagonists are useful in reducing the incidence of stroke. (see A.J.Kaumann1990, Naumyn-Schmiedeberg's Arch.Pharmacol.342, 619-.

Accordingly, the present invention further provides a method of treatment for irritable bowel syndrome, gastroesophageal reflux disease, dyspepsia, atrial arrhythmia, stroke and ischemic stroke, anxiety, migraine, alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, atrial fibrillation, gastritis, gastric emptying disorders, eating disorders, gastrointestinal disorders, constipation, erectile dysfunction and/or respiratory depression in a mammal, such as a human, comprising administering an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the methods include treating IBS or atrial arrhythmia and stroke.

Compound of the present invention para 5-HT₄The 5-hydroxytryptamine receptor has high affinity and specificity. They are capable of stimulating or inhibiting at the central or peripheral level those effects mediated by the activation of this receptor subtype. Thus, a compound of the invention may be defined as 5-HT₄Novel agonists or partial agonists, antagonists or inverse agonists of the receptor in vivo and in vitro. 5-HT₄The receptors belong to the family of 5-hydroxytryptamine-capable receptors, and they belong to those more recently discovered, pharmacologically characterized and cloned. 5-HT after first identification of discrete regions of the guinea pig CNS₄The 5-hydroxytryptamine receptors have also been localized in other regions, centers or distal (ileum, atrium, esophagus, colon, bladder and adrenal gland) of different species including humans. These receptors, present in different organs and tissues, make it possible for compounds to prevent their hyperstimulation, and thus can be advantageously used for the treatment and prevention of different pathological conditions.

Thus, for example, due to 5-HT₄The stimulation of atrial cardiac receptors, in addition to causing inotropic and chronotropic positive responses, can also lead to arrhythmias observed in some experimental conditions, and therefore antagonists of these receptors are useful in the specific treatment of arrhythmic disorders such as atrial fibrillation and other types of arrhythmias. In the gastrointestinal tract, due to 5-HT₄Receptor-mediated prokinetic movement of 5-hydroxytryptamineAnd secretion, which suggests the use of 5-HT₄Antagonists treat disorders associated with altered bowel movement or secretion, such as IBS, and more particularly those forms of IBS that are combined with diarrhea states. 5-HT₄The presence of receptors in the central nervous system of rats or humans may be restricted to specific areas such as the hippocampus, prefrontal cortex, basal ganglia and limbic structures. Thus, 5-HT can be controlled₄Compounds whose receptors are altered by stimulation in the CNS may be used in psychiatric and neurological fields such as alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, irritable bowel syndrome, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, or respiratory depression. Furthermore, since 5-HT has already been described₄The receptor moiety mediates the role of 5-HT in controlling ethanol uptake, thus 5-HT₄The antagonists may be used to treat alcohol abuse. 5-HT₄Receptors are also involved in controlling other functions of the urogenital and adrenal systems, where they appear to mediate the release of steroid hormones. Thus, it is useful to block 5-HT₄Compounds of the receptor are useful in the treatment of pathological conditions characterized by altered hormone secretion or urinary incontinence.

The present invention relates to the discovery that novel compounds that are 5-HT modulators, such as agonists, partial agonists, antagonists and/or SSRIs, can be used to treat, prevent or cure 5-HT associated diseases. In particular, certain thienopyridinone compounds have been found to be potent 5-HT receptor modulators, more particularly 5-HT₄，5-HT_4aAnd 5-HT_4eReceptor modulators and/or SSRIs.

The compounds of the present invention include those having the formula:

wherein

R₁May be ethyl or isopropyl; and R is₂Optionally substituted alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, methylcyclopropyl, isopropyl alcohol, phenethyl.

The compounds of the present invention also include those having the formula:

wherein:

R₁may be (C)₁-C₈) A branched or unbranched alkyl or alkenyl group; (C)₁-C₈) A substituted or unsubstituted carbocyclic ring; a substituted or unsubstituted aryl or heteroaryl ring; with branched or unbranched haloalkyl groups (e.g. CF)₃、CF₃-CH₂、CF₃-CF₂-) according to the formula (I); or substituted or unsubstituted (CH)₂)_p-aryl or (CH)₂)_p-a heteroaryl ring, wherein p is 1, 2, 3 or 4; and is

R₂May be optionally substituted (C)₁-C₆) With branched or unbranched alkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy or alkanoyl groups. R₂Suitable substituents above include substituted or unsubstituted aryl; a hydroxyl group; (C)₁-C₆) A substituted or unsubstituted carbocyclic ring; substituted or unsubstituted (C)₁-C₆) Alkylhydroxy, substituted or unsubstituted (C)₁-C₆) Alkylalkoxy, substituted or unsubstituted (C)₁-C₆) Alkylamino, substituted or unsubstituted (C)₁-C₆) Alkylaminoacyl, substituted or unsubstituted (C)₁-C₆) An alkylamino aryl group.

Suitable R₂The groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl.

The compounds of the present invention may also be 5-HT receptor antagonists, such as 5-HT₄A receptor antagonist.

In another embodiment, the compounds of the invention may also be partial agonists of the 5-HT receptor, e.g., 5-HT₄，5-HT_4a 5-HT_4eA receptor partial agonist.

In another embodiment, the compounds of the invention may also be 5-HT receptor agonists, such as 5-HT₄A receptor agonist.

In another embodiment, the compounds of the invention may also be 5-HT receptor inverse agonists, such as 5-HT₄Receptor inverse agonists.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula I or II in an amount effective to treat a central nervous system disorder in a mammal suffering from the disorder, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating a central nervous system disorder in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula I or II.

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula I or II effective to treat alzheimer's disease in a mammal suffering from the disease and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating Alzheimer's disease in a mammal, such as a human, which comprises administering a therapeutically effective amount of a compound of formula I or II.

Another aspect of the invention is a pharmaceutical composition comprising a memory enhancing effective amount of a compound of formula I or II and a pharmaceutically acceptable carrier for enhancing memory in a mammal in need of memory enhancement.

Another aspect of the invention is a method for memory enhancement in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula I or II.

Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound of formula I or II for treating Irritable Bowel Syndrome (IBS) and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating Irritable Bowel Syndrome (IBS) comprising administering a therapeutically effective amount of a compound of formula I or II.

Also included in the invention are methods of preparing the compounds and novel intermediates.

The compounds of the present invention are valuable for the treatment of a wide variety of clinical conditions characterized by 5-hydroxytryptamine excess or deficiency, such as hypofunction or hyperactivity of 5-hydroxytryptamine. These conditions include schizophrenia and other psychotic disorders such as schizophrenia, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; gastrointestinal disorders such as Crohn's disease, eating disorders, neuropathic pain and addiction disorders; obsessive-compulsive disorder, phobias, central nervous system-induced sexual dysfunction and disorders of sleep and food absorption, alcoholism, pain, memory deficits, unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in medical conditions, phobias, obsessive-compulsive disorder, eating disorders, social phobias, premenstrual dysphoric disorder, mood disorders such as depression or more specific depressive disorders, e.g. single-or recurrent major depressive disorder and dysthymic disorder, or bipolar disorders such as bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, phobias with or without agoraphobia, agoraphobia without history of phobias, specific phobias, such as specific animal phobias, social phobia, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder; confusion, dementia and amnestic disorders as well as other cognitive or neurodegenerative disorders such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and others such as dementia due to HIV disease, brain damage, Parkinson's disease, Huntington's disease, pick's disease, Creutzfeldt-Jakob disease, or dementia due to multiple etiologies; parkinson's disease and other extrapyramidal movement disorders such as, drug therapy-induced movement disorders such as neuroleptic-induced Parkinson's disease, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug therapy-induced postural tremor; substance-related disorders caused by the use of alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants and spray propellants, nicotine, opioids, phenylglycine derivatives, sedatives, hypnotics and anxiolytics, including dependence and abuse, intoxication, withdrawal, toxic delirium, withdrawal delirium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; down syndrome; demyelinating diseases such as MS and ALS and other neuropathic disorders, such as peripheral neuropathies, e.g. diabetes and chemotherapy-induced neuropathies, post-herpetic neuralgia, trigeminal neuralgia, partial or interpulse neuralgia and other neuralgia; cerebrovascular disorders induced by acute or chronic cerebrovascular injury such as cerebral infarction, subarachnoid hemorrhage or cerebral edema.

The compounds of the invention may be used in the treatment of the above diseases, as well as in the treatment of vasodilation, smooth muscle contraction, bronchoconstriction, cerebral disorders such as vascular disorders, for example, vasodilation and vasospastic diseases such as angina, vascular headache, migraine and blood flow disorders caused by Reynaud's disease; pulmonary hypertension and systemic hypertension; and neuropathic disorders including Parkinson's disease and Alzheimer's disease; modulation of the cardiovascular system; prevention and control of the effects of the onset of cerebral infarction (stroke) such as stroke or cerebral ischemia; and for the control of intestinal disorders characterized by disturbances of the 5-hydroxytryptamine energy system and disturbances of carbohydrate metabolism.

The compounds of the invention may also be useful in the treatment of a variety of other diseases, including stress-related somatic disorders, reflex sympathetic dystrophy such as shoulder/hand syndrome; bladder dysfunction, such as cystitis, bladder detrusor hyperreflexia, and incontinence; pain or nociception caused by or associated with any of the above-mentioned diseases, particularly pain transmission in migraine.

For the treatment of certain diseases, it may be desirable to use the compounds of the present invention in combination with other pharmacologically active agents. The compounds of the invention may be provided as a combined preparation with other therapeutic agents for simultaneous, separate or sequential use. These combination preparations may be, for example, in the form of a pair pack.

A further aspect of the invention includes the use of a compound of the invention in combination with one or another 5-HT antagonist and/or an SSRI, e.g. 5-HT₃Antagonists, such as ondansetron, granisetron, tropisetron or zatosetron. In addition, the compounds of the present invention may also be administered in combination with an anti-inflammatory corticosteroid such as dexamethasone. Furthermore, the compounds of the present invention may be administered in combination with chemotherapeutic agents, such as the alkylating agents described above, antimetabolites, mitotic inhibitors or cytotoxic antibiotics. In general, the currently available dosage forms of known therapeutic agents for use in such combinations would be suitable.

According to a further or alternative aspect, the present invention provides a compound of the invention for use in the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess or deficiency of 5-hydroxytryptamine, such as hypo-or hyper-function of 5-hydroxytryptamine.

The present invention also provides a method for treating or preventing a physiological disorder associated with excess or deficiency of 5-hydroxytryptamine, such as hypofunction or hyperactivity of 5-hydroxytryptamine, comprising administering to a patient in need thereof an effective amount of a compound of the present invention or a composition comprising a compound of the present invention.

For the treatment or prevention of migraine, the compounds of the present invention may be combined with other anti-migraine agentsCombinations of pain medications, e.g. ergotamines or 5-HT₁Agonists, especially sumatriptan or rizatriptan. Similarly, for the treatment of behavioral hyperalgesia, the compounds of the present invention may be administered in combination with an antagonist of N-methyl D-aspartate (NMDA), such as dezocine.

The compounds of the present invention and other pharmacologically active agents may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that where a combination of the invention is used, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceutically acceptable carrier and therefore may be administered simultaneously. They may be in a separate pharmaceutical carrier, as in a conventional oral dosage form taken simultaneously. The term "combination" further refers to the situation where the compounds are provided in separate dosage forms and administered sequentially.

The compounds of the invention can be administered to patients (animals and humans) in need of such treatment in dosages that will achieve optimal pharmaceutical efficacy. It will be appreciated that the dosage required for any particular application will vary from patient to patient, not only with respect to the particular compound or composition selected, but also with respect to the route of administration, the nature of the condition being treated, the age and condition of the patient, the particular diet or drugs being followed by the patient concurrently, and other factors which will be recognized by those skilled in the art, the appropriate dosage ultimately being determined by the attending physician.

In the treatment of conditions associated with excess or deficiency of 5-hydroxytryptamine, such as hypo-or hyper-function of 5-hydroxytryptamine, suitable dosage levels are generally in the range of about 0.001-50mg/kg of patient body weight per day, and may be administered in single or multiple doses. Preferably, the dosage level is from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day. For example, in the treatment or prevention of central nervous system disorders, suitable dosage levels are about 0.001-10 mg/kg/day, preferably about 0.005-5 mg/kg/day, especially about 0.01-1 mg/kg/day. The dosing regimen of the compounds of the invention may be 1-4 times per day, preferably 1 or 2 times per day.

It will be understood that the dosage of the compound of the invention required for use in any treatment will vary, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, and will ultimately be at the appropriate dosage determined by the attending physician.

The compositions and combination therapies of the present invention can be administered with a wide variety of pharmaceutical excipients, including stabilizers, carriers, and/or encapsulated formulations as described herein.

The aqueous compositions of the invention comprise an effective amount of a peptide of the invention dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous vehicle.

"pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that, when administered to an animal or human, do not produce adverse, allergic, or other untoward reactions, if desired. "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antibacterial agents, isotonic and absorption delaying agents, and the like. The use of such vehicles and substances for pharmaceutically active substances is well known in the art. Any conventional vehicle or substance, so long as it is not incompatible with the active ingredient, is contemplated for use in the therapeutic compositions. Supplementary active ingredients may also be incorporated into the composition.

For human administration, the formulations should meet sterility, pyrogenicity, general safety and purity standards as defined in FDA office of biologies standards.

The compositions and combination therapies of the present invention are generally formulated for parenteral administration, e.g., by intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The formulation of aqueous compositions containing the compositions or active ingredients or ingredients of the present invention will be well known to those skilled in the art in light of this disclosure. Typically, these compositions are formulated as injections, liquid solutions or suspensions; solid forms suitable for solution or suspension upon addition of a liquid prior to injection may also be prepared; and these formulations can also be emulsified.

Pharmaceutical dosage forms suitable for injection include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the dosage form must be sterile and capable of flowing to the extent that it can be readily injected. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The therapeutic or pharmacological compositions of the invention generally comprise an effective amount of the components of the combination therapy dispersed or dissolved in a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles or carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such vehicles and drugs for pharmaceutically active substances is well known in the art. Supplementary active ingredients may also be incorporated into the therapeutic compositions of the present invention.

The preparation of pharmaceutical or pharmacological compositions is well known to those skilled in the art in light of the present disclosure. Typically, these compositions are prepared as injectables, liquid solutions or suspensions; solid forms suitable for dissolution or suspension in a liquid prior to injection; tablets or other solid forms for oral administration; a time release capsule; or any other dosage form currently used, including creams, lotions, mouthwashes, inhalants, and the like.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which includes a basic dispersion vehicle and the required other ingredients from those enumerated above. In the case of sterile powdered medicaments for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any other desired ingredient in their previously sterile-filtered solution.

It is also contemplated to prepare more, or highly concentrated, solutions for intramuscular injection. In this connection, it is preferred to use DMSO as solvent, since this will lead to very rapid penetration, allowing a high concentration of the active compound or agent to be delivered into a small area.

It is also useful for the surgeon, physician, or medical caregiver to use a sterile formulation, such as a saline-based wash solution, in order to clean a particular area of the operating area. The therapeutic formulations of the present invention may also be reconstituted as mouthwash or used in combination with antifungal agents. Inhalation forms are also contemplated. The therapeutic formulations of the present invention may also be formulated in dosage forms suitable for topical administration, such as creams and lotions.

Suitable preservatives for use in such solutions include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal, and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium hydrogen phosphate, and the like, in amounts sufficient to maintain a pH of about 6 to about pH 8, preferably about pH 7 to about pH 7.5. Suitable isotonic agents are dextran 40, dextrose 70, glucose, glycerol, potassium chloride, propylene glycol, sodium chloride, and the like, such that the equivalent range of sodium chloride in the ophthalmic solution is 0.9 ± 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282, and tyloxapol. Suitable viscosity increasing agents include dextran 40, dextran 70, gelatin, glycerol, hydroxyethyl cellulose, hydroxymethyl propyl cellulose, lanolin, methyl cellulose, paraffin oil, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, and the like.

After formulation, the therapeutic agent is administered in a manner compatible with the dosage form in an amount that is pharmacologically effective. The formulations are readily administered in a variety of different dosage forms, such as injectable solutions of the type described above, but drug-releasing capsules and the like may also be used.

In this context, the amount of active ingredient and the volume of the composition administered depend on the host animal to be treated. The precise amount of active compound required to be administered will depend on the judgment of the practitioner and will be specific to each individual.

Typically with the minimum amount of composition required to disperse the active compound. Suitable dosing regimens vary, but typically the compound is administered initially and the results monitored, followed by further controlled doses given at further intervals. For example, for parenteral administration, suitably buffered, and if desired, isotonic aqueous solutions will be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. One dose can be dissolved in 1ml of isotonic NaCl solution and added to 1000ml of subcutaneous infusion liquid or injected at the proposed infusion site. (see, e.g., Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580).

In certain embodiments, the active compound may be administered orally. This is contemplated for agents that are generally resistant to proteolysis by digestive enzymes or that have been rendered resistant to proteolysis by digestive enzymes. It is contemplated that these compounds include agents that are chemically designed or modified; a dextrorotatory peptide; peptide and liposome formulations that avoid degradation of peptidases and lipases in time release capsules.

Pharmaceutically acceptable salts include acid addition salts which are formed with inorganic acids such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, maleic, fumaric, citric, succinic, methanesulfonic, mandelic, succinic, benzoic, ascorbic, methanesulfonic, a-ketoglutaric, a-glycerophosphoric, glucose-1-phosphoric acids and the like. The salts with free carboxyl groups can also be formed from inorganic bases, e.g. sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxideMagnesium hydroxide, or ferric hydroxide, and from organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like. Examples of other pharmaceutically acceptable salts include quaternary ammonium salt derivatives of the compounds of formula (I), such as the compound R_x-T quaternized compounds wherein R_xIs C_1-6Alkyl, phenyl-C_1-6Alkyl or C_5-7Cycloalkyl, T is the radical corresponding to the anion of the acid. Suitable R_xExamples of (b) include methyl, ethyl, n-and i-propyl; and benzyl and phenethyl. Examples of suitable T include halides, such as chloride, bromide or iodide. Examples of other pharmaceutically acceptable salts also include internal salts such as N-oxides.

The carrier can also be a solvent or dispersion vehicle, including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterilized medium which contains the basic dispersion vehicle and the required other ingredients from those enumerated above. In the case of sterile powdered medicaments for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any other desired ingredient in a previously sterile-filtered solution thereof.

It is also contemplated to prepare more concentrated, or highly concentrated, solutions for direct injection, where it is contemplated to use DMSO as a solvent to produce very rapid penetration, allowing high concentrations of the active agent to be delivered into a small area.

After formulation, the solution will be administered in a manner compatible with the dosage form and in an amount that is therapeutically effective. The formulations are readily administered in a variety of different dosage forms, such as injectable solutions of the type described above, but drug-releasing capsules and the like may also be used.

For parenteral administration with an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, sterile aqueous vehicles that can be used in accordance with the present disclosure are well known to those skilled in the art.

In addition to formulating the compounds for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable dosage forms include, for example, tablets or other solids for oral administration; a liposome formulation; time release capsules and any other dosage form currently in use, including creams.

Other formulations suitable for other modes of administration include suppositories. For suppositories, conventional binders and carriers may include, for example, polyethylene glycols or triglycerides; these suppositories may be made of a mixture containing the active ingredient in an amount of 0.5% to 10%, preferably 1% to 2%.

Oral formulations include such conventional excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.

In some defined embodiments, oral pharmaceutical compositions contain an inert diluent or an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, troches, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. These compositions and preparations should contain at least 0.1% of active compound. The composition and percentage of formulation may of course vary and may suitably be from about 2 to about 75%, preferably 25 to 60%, by weight of the unit. The amount of active compound in such therapeutically effective compositions is such that a suitable dosage will be obtained.

Tablets, troches, pills, capsules and the like may also include the following ingredients: binders, such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactose or saccharin may be added or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. Where the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be provided as coatings or otherwise modify the physical form of the dosage unit. For example, tablets, pills, capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

The pharmaceutical compositions of the invention may be employed in the form of pharmaceutical preparations, e.g. in solid, semi-solid or liquid dosage forms containing one or more compounds of the invention as active ingredient, in admixture with organic or inorganic carriers or excipients, suitable for topical, enteral or parenteral administration.

The active ingredient may be combined with conventional non-toxic pharmaceutically acceptable carriers for forming tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and other dosage forms suitable for use. Carriers which may be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea and other carriers suitable for the preparation of preparations in solid, semi-solid or liquid form, and in addition adjuvants, stabilizers, thickeners, colorants and flavoring agents. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, such as conventional tableting ingredients, e.g. corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. These solid preformulation compositions may then be subdivided into unit dosage forms of the type described above containing from 0.1 to about 500mg of the active ingredient of the present invention. The tablets or pills of the novel compositions may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may contain an inner and an outer dosage component, the latter being in the form of a film coating on the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, to maintain the inner component intact in the duodenum, or to delay release. Such enteric layers or coatings may be formed from a variety of materials including polymeric acids in large amounts and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid dosage forms in which the compositions of the present invention may be incorporated for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, emulsions with acceptable oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil or with solubilizing or emulsifying agents suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include liquids and suspensions in pharmaceutically acceptable water or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. Preferably the composition is administered by the oral or nasal respiratory route to achieve local or systemic effect. Preferably, the composition in a sterile pharmaceutically acceptable solvent can be nebulized using an inert gas. The nebulized solution can be breathed directly through the nebulizing device or the nebulizing device can be attached to a mask, tent, or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered from a device which delivers the formulation in a suitable manner, preferably orally or nasally.

For the treatment of the above-mentioned clinical conditions and diseases, the compounds of the present invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Methods for preparing the compounds of the present invention are illustrated in the following synthetic schemes and examples. The following schemes, examples and biological data are given only for illustrating the present invention and are not to be construed as limiting the scope or spirit of the present invention.

Synthesis of novel thienopyridinone compounds

The novel thienopyridone compounds of the present invention were synthesized as shown below.

Novel thienopyridinone compounds of general structure 1 can be synthesized by a coupling reaction between amine 2 and ester 3 as shown in scheme 1 below.

Scheme 1

More specifically, the compounds disclosed herein (wherein m ═ 0 and n ═ 1) were synthesized according to the reaction sequences exemplified in schemes 2 and 3. In step A, with an alkyl halide (R)₄X, X ═ Br or I) and potassium carbonate in DMF to N-alkylate N-Boc-4-aminopiperidine (4), followed by treatment with trifluoroacetic acid (TFA) in dichloromethane to afford R₄-substituted 4-aminopiperidine bis-TFA salt 2 a. In the general structure 1, R₁And R₂May include H; r₃It may include ethyl or isopropyl groups and Me, Et, n-Pr, i-Pr, n-Bu, i-Bu. R₄Can include Me, Et, n-Pr, i-Pr, CH₂-cyclopropyl, N-Bu, i-By, s-Bu, N-pentyl, benzyl, phenethyl, N-3-hydroxypropyl, N-4-hydroxybutyl, N-2-hydroxypropyl or N-5-hydroxypentyl.

Scheme 2

In step B, substituted or unsubstituted 2-aminothiophene-3-carboxylate (6) is reductively alkylated with an aldehyde, ketone or dimethoxyketal to give alkylation product 7. In step C, 7 is converted to the ester intermediate 3 in a two-step sequence: the amide was formed using ethyl 3-chloro-3-oxopropionate and triethylamine, followed by intramolecular condensation in the presence of sodium methoxide. In step D, ester 3 is reacted with 2a in the presence of diisopropylethylamine while heating at reflux in xylene to give 1 a.

Scheme 3

And B: aldehydes, ketones or dimethyl ketals, NaBH (OAc)₃，CH₂Cl₂TFA, AcOH; and C: ClC (═ O) CH₂CO₂Et，Et₃N，CH₂Cl₂Then NaOMe, MeOH; step D: 2a, i-Pr₂NEt, xylene, reflux

Experiment of

Example 1

6, 7-dihydro-N- (1-ethylpiperidin-4-yl) -4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide hydrochloride

Step A: preparation of 1-ethylpiperidin-4-amine

Ethyl iodide (0.18mL, 2.3mmol) was added to a suspension of N-Boc-4-aminopiperidine (0.5g, 2.5mmol) and potassium carbonate (0.69g, 4.6mmol) in DMF (10 mL). The reaction mixture was stirred for 16 hours and concentrated under reduced pressure. The residue was dissolved in water and extracted with ether; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an off-white solid (0.53 g). The solid was treated with trifluoroacetic acid (5mL) in dichloromethane (10mL) for 2 hours. The reaction mixture was concentrated under reduced pressure; the residue was co-evaporated with hexane to remove excess trifluoroacetic acid to give the title compound as a light brown oil.

And B: preparation of methyl 2- (isopropylamino) thiophene-3-carboxylate

To a solution of methyl 2-aminothiophene-3-carboxylate (1.76kg, 11.2mol) in glacial acetic acid (1.34kg, 22.3mol) and dichloromethane (8L) were added trifluoroacetic acid (17.8g, 156mmol), 2-dimethoxypropane (6.83kg, 65.6mmol) and sodium triacetoxyborohydride (3.9kg, 18.4 mol). The reaction mixture was stirred at room temperature for 18 hours, quenched with saturated aqueous potassium carbonate (13.5L) over 3 hours and diluted with water (21L). The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 × 6 kg). The combined extracts were washed with aqueous sodium chloride solution (10kg) and concentrated under reduced pressure to give a dark black-red liquid (2.4 kg). Purifying with 15-kg silica gel flash chromatography columnThe residue, eluting with 3% ethyl acetate-heptane, gave the title compound as a light yellow liquid.¹H NMR(400MHz，CDCl₃)：δ7.00(d，1H)，6.15(d，1H)，3.80(s，3H)，3.51(m，1H)，1.30(d，6H)。

And C: preparation of methyl 6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno- [2, 3-b ] pyridine-5-carboxylate

To a solution of methyl 2- (isopropylamino) thiophene-3-carboxylate (3.50g, 17.6mmol) in dichloromethane (50mL) at 0 deg.C was added triethylamine (5.33g, 52.8mmol), followed by ethyl 3-chloro-3-oxopropanoate (3.96g, 26.3 mmol). The reaction mixture was warmed to room temperature, stirred for 2 hours, concentrated and dissolved in ethyl acetate. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated to give a dark red oily residue (3.50 g). To a solution of the residue in methanol (40mL) at room temperature was added freshly sliced sodium metal (0.77g, 33.5mmol) in portions to moderate the reflux. After the addition was complete, the reaction mixture was heated at reflux for 18 hours, cooled to room temperature and concentrated. Dissolving the residue in water; the resulting solution was washed with dichloromethane, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residual solid was recrystallized from ether to give the title compound as an off-white solid (1.92g, yield 41%).¹H NMR(400MHz，CDCl₃)：δ13.84(s，1H)，7.33(d，1H)，6.91(d，1H)，4.83(br，1H)，4.01(s，3H)，1.63(d，6H)。

Step D: preparation of 6, 7-dihydro-N- (1-ethylpiperidin-4-yl) -4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide

Reacting 6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno- [2, 3-b]A solution of pyridine-5-carboxylic acid methyl ester (0.22g, 0.82mmol), 1-ethylpiperidin-4-amine (0.44g, 1.24mmol) and diisopropylethylamine (0.35mL, 2.48mmol) in xylene (3mL) was heated at 120 ℃ for 2 hours. The reaction mixture was cooled to room temperature, washed with water and concentrated under reduced pressure. By using a catalyst based on siliconThe residue was purified by gel flash column chromatography eluting with 3% methanol-dichloromethane to give the title compound (0.20g, yield 67%) as an off-white solid.¹H NMR(400MHz，CDCl₃)：δ10.34(br s，1H)，7.37(d，1H)，6.95(d，1H)，4.01(m，2H)，3.03(m，2H)，2.63(d，2H)，2.41(m，2H)，2.12(d，2H)，1.81(q，2H)，1.62(d，6H)，1.18(t，3H)；MS：m/e 364(M+H⁺)。

Example 2

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-propylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that in step a, ethyl iodide was replaced with propyl iodide.

¹H NMR(400MHz，CDCl₃)：δ10.30(br s，1H)，7.40(d，1H)，6.98(d，1H)，4.00(br，1H)，2.95(m，2H)，2.60-1.50(m，10H)，1.60(d，6H)，0.98(t，3H)；MS：m/e 378(M+H⁺)。

Example 3

N- (1-butylpiperidin-4-yl) -6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno [2, 3-h ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, but substituting butyl iodide for ethyl iodide in step a.

¹H NMR(400MHz，CDCl₃)：δ10.25(br s，1H)，7.37(d，1H)，6.94(d，1H)，3.96(m，2H)，2.85(m，2H)，2.35(dd，2H)，2.17(t，2H)，2.02(d，2H)，1.73-1.61(m，7H)，1.49(m，2H)，1.34(m，2H)，0.92(t，3H)；MS：m/e 392(M+H⁺)。

Example 4

6, 7-dihydro-4-hydroxy-N- (1- (3-hydroxypropyl) piperidin-4-yl) -7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, but substituting 3-iodopropan-1-ol for ethyl iodide in step A.

¹H NMR(400MHz，CDCl₃)：δ10.27(br s，1H)，7.37(d，1H)，6.94(d，1H)，3.98(br，1H)，3.82(t，2H)，3.00(m，2H)，2.64(t，2H)，2.20(m，2H)，2.04(d，2H)，1.76-1.62(m，10H)；MS：m/e 394(M+H⁺)。

Example 5

N- (1- (cyclopropylmethyl) piperidin-4-yl) -6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that cyclopropylmethyl bromide was used instead of ethyl iodide in step a.

¹H NMR(400MHz，CDCl₃)：δ10.50(br s，1H)，7.39(d，1H)，6.99(d，1H)，4.10(br，1H)，3.91-3.80(m，1H)，2.98-2.30(m，4H)，2.20(d，2H)，1.83-1.52(m，4H)，1.60(d，6H)，0.84-0.80(m，1H)，0.60-0.30(m，2H)，0.20(m，2H)；MS：m/e 390(M+H⁺)。

Example 6

6, 7-dihydro-4-hydroxy-N- (1-isobutylpiperidin-4-yl) -7-isopropyl-6-oxothieno [2, 3-h ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that in step a the ethyl iodide was replaced with isobutyl iodide.

¹H NMR(400MHz，CDCl₃)：δ10.27(br s，1H)，7.39(d，1H)，6.98(d，1H)，4.00(br，1H)，2.93(d，2H)，2.60-1.50(m，8H)，1.60(d，6H)，1.24(m，1H)，0.90(d，6H)；MS：m/e 392(M+H⁺)。

Example 7

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-phenethylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that phenethyl bromide was used instead of ethyl iodide in step a.

¹H NMR(400MHz，CDCl₃)：δ10.28(br s，1H)5 7.37(d，1H)，7.31-7.26(m，2H)，7.23-7.19(m，3H)，6.94(d，1H)，3.99(m，1H)，2.93(d，2H)，2.82(dd，2H)，2.63(dd，2H)，2.29(t，2H)，2.05(d，2H)，1.76-1.62(m，8H)；MS：m/e 440(M+H⁺)。

Example 8

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-pentylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that in step a the ethyl iodide was replaced with pentyl iodide.

¹H NMR(400MHz，CDCl₃)：δ10.23(br s，1H)，7.36(d，1H)，6.93(d，1H)，3.95(m，1H)，2.84(m，2H)，2.32(m，2H)，2.19-1.93(m，4H)，1.72-1.60(m，8H)，1.53-1.43(m，2H)，1.36-1.22(m，4H)，0.89(t，3H)；MS：m/e 406(M+H⁺)。

Example 9

6, 7-dihydro-7-ethyl-4-hydroxy-6-oxo-N- (1-propylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that ethyl iodide was replaced with propyl iodide in step a and 2, 2-dimethoxypropane was replaced with acetaldehyde in step B, without the use of trifluoroacetic acid.

¹H NMR(400MHz，CDCl₃)：δ10.20(br s，1H)，7.36(d，1H)，6.95(d，1H)，4.15(q，2H)，3.96(m，1H)，2.85(m，2H)，2.32(m，2H)，2.20(t，2H)，2.03(m，2H)，1.72(m，2H)，1.53(m，2H)，1.40(t，3H)，0.89(t，3H)；MS：m/e 364(M+H⁺)。

Example 10

6, 7-dihydro-7-ethyl-4-hydroxy-N- (1- (3-hydroxypropyl) piperidin-4-yl) -6-oxothieno [2, 3-b ] pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlined in example 1, except that 3-iodopropan-1-ol was used in place of ethyl iodide in step a and acetaldehyde was used in place of 2, 2-dimethoxypropane in step B, without the use of trifluoroacetic acid.

¹H NMR(400MHz，CDCl₃)：δ10.20(br s，1H)，7.36(d，1H)，6.95(d，1H)，4.15(q，2H)，3.96(m，1H)，3.00(m，2H)，2.82(t，2H)，2.64(t，2H)，2.20(m，2H)，2.03(m，2H)，1.72-1.62(m，4H)，1.40(t，3H)；MS：m/e 380(M+H⁺)。

Biological activity of thienopyridone derivatives

The compounds of the invention synthesized as above and their reaction with 5-HT were determined_4eBinding affinity of the receptor. The biological activity of the novel thienopyridone derivatives is shown in table 1.

Table 1: novel thienopyridone derivatives in 5-HT_4eBiological activity in receptor assays

Thus, these novel compounds are expected to be useful as potent and selective 5-HT₄Receptor modulators, e.g. for the treatment of a wide variety of clinical conditions including alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, emesis, prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, eating disorders, gastrointestinal disorders, constipation, erectile disorders, respiratory depression, which conditions are characterized by excess or deficiency of 5-hydroxytryptamine, e.g. hypo-5-hydroxytryptamine energy or hyperfunction.

Equivalent scheme

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. Various substitutions, and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the invention. The contents of all references, issued patents and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes and methods of those patents, publications and other documents may be selected for use in the present invention and embodiments thereof.

Claims (31)

1. A compound having the formula:

wherein

·R₁Is ethyl or isopropyl; and is

·R₂Is an optionally substituted alkyl group selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, methylcyclopropyl, isopropylPropanol, phenethyl.

2. The compound of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate, fumarate, succinate, tartrate, mesylate, sodium, potassium, magnesium, and calcium salts.

3. The compound of claim 1, wherein the compound is 5-HT₄A receptor antagonist.

4. The compound of claim 1, wherein the compound is 5-HT₄A receptor agonist.

5. The compound of claim 1, wherein the compound is 5-HT₄A receptor partial agonist.

6. The compound of claim 1, wherein the compound is h5-HT_4aA receptor partial agonist.

7. The compound of claim 1, wherein the compound is h5-HT_4eA receptor partial agonist.

8. The compound of claim 1, wherein the compound is h5-HT_4aA receptor agonist.

9. The compound of claim 1, wherein the compound is h5-HT_4eA receptor agonist.

10. The compound of claim 1, wherein the compound is 5-HT₄Receptor inverse agonists.

11. A pharmaceutical composition comprising an effective CNS or peripheral nervous system disorder treating amount of a compound of claim 1.

12. The pharmaceutical composition of claim 11, wherein said CNS or peripheral nervous system disorder is selected from the group consisting of alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.

13. A method of treating a CNS or peripheral nervous system disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound of claim 1 to treat said CNS or peripheral nervous system disorder.

14. The method of claim 13, wherein said CNS or peripheral nervous system disorder is selected from the group consisting of alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.

15. A method of treating a CNS or peripheral nervous system disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising an amount of a compound of formula II effective to treat said CNS or peripheral nervous system disorder:

wherein

·R₁Is (C)₁-C₈) A branched or unbranched alkyl or alkenyl group; (C)₁-C₈) A substituted or unsubstituted carbocyclic ring; substituted or unsubstituted aryl orA heteroaryl ring; with branched or unbranched haloalkyl groups (e.g. CF)₃、CF₃-CH₂、CF₃-CF₂-) according to the formula (I); or substituted or unsubstituted (CH)₂)_p-aryl or (CH)₂)_p-a heteroaryl ring, wherein p is 1, 2, 3 or 4; and is

·R₂Is optionally substituted (C)₁-C₆) With branched or unbranched alkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy or alkanoyl groups.

16. The method of claim 13, wherein said CNS or peripheral nervous system disorder is selected from the group consisting of alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.

17. The method of claim 15, wherein said CNS or peripheral nervous system disorder is selected from the group consisting of alzheimer's disease, cognitive disorders, irritable bowel syndrome, parkinson's disease, nausea, vomiting, emesis, prokinesia, gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.

18. A method for treating irritable bowel syndrome, comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of claim 1 in an amount effective to treat said irritable bowel syndrome.

19. A method for treating irritable bowel syndrome, comprising administering to a patient in need thereof a pharmaceutical composition comprising an amount of a compound of formula II effective to treat said CNS or peripheral nervous system disorder:

wherein

·R₁Is (C)₁-C₈) A branched or unbranched alkyl or alkenyl group; (C)₁-C₈) A substituted or unsubstituted carbocyclic ring; a substituted or unsubstituted aryl or heteroaryl ring; with branched or unbranched haloalkyl groups (e.g. CF)₃、CF₃-CH₂、CF₃-CF₂-) according to the formula (I); or substituted or unsubstituted (CH)₂)_p-aryl or (CH)₂)_p-a heteroaryl ring, wherein p is 1, 2, 3 or 4; and is

·R₂Is optionally substituted (C)₁-C₆) With branched or unbranched alkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy or alkanoyl groups.

20. A method of treating alzheimer's disease comprising administering to a patient in need thereof a pharmaceutical composition comprising an amount of a compound of claim 1 effective to treat said alzheimer's disease.

21. A method of treating alzheimer's disease comprising administering to a patient in need thereof a pharmaceutical composition comprising an amount of a compound of formula II effective to treat said CNS or peripheral nervous system disorder:

wherein

·R₁Is (C)₁-C₈) A branched or unbranched alkyl or alkenyl group; (C)₁-C₈) A substituted or unsubstituted carbocyclic ring; a substituted or unsubstituted aryl or heteroaryl ring; with branched or unbranched haloalkyl groups (e.g. CF)₃、CF₃-CH₂、CF₃-CF₂-) according to the formula (I); or substituted or unsubstituted (CH)₂)_p-aryl or (CH)₂)_p-a heteroaryl ring, wherein p is 1, 2, 3 or 4; and is

·R₂Is optionally substituted (C)₁-C₆) With branched or unbranched alkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy or alkanoyl groups.

6, 7-dihydro-N- (1-ethylpiperidin-4-yl) -4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-propylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

N- (1-butylpiperidin-4-yl) -6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-4-hydroxy-N- (1- (3-hydroxypropyl) piperidin-4-yl) -7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

N- (1- (cyclopropylmethyl) piperidin-4-yl) -6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-4-hydroxy-N- (1-isobutylpiperidin-4-yl) -7-isopropyl-6-oxothieno [2, 3-b ] ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-phenethylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N- (1-pentylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-7-ethyl-4-hydroxy-6-oxo-N- (1-propylpiperidin-4-yl) thieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.

6, 7-dihydro-7-ethyl-4-hydroxy-N- (1- (3-hydroxypropyl) piperidin-4-yl) -6-oxo-thieno [2, 3-b ] pyridine-5-carboxamide and pharmaceutically acceptable salts thereof.