Methods and compositions for treatment of central and peripheral nervous system disorders and novel compounds useful therefor

Abstract

There are provided methods for the treatment of diseases involving dysfunction of the peripheral and central nervous system comprising administering one or more spiro compounds. Also provided are pharmaceutical compositions useful in such methods, compounds for use in the preparation of such pharmaceutical compositions, processes for preparing compounds useful in the practice of such methods, and some novel such compounds per se.

1 .- 130 . (canceled) 
   
   
       131 . A method of preventing or treating a disease or disorder associated with M1 muscarinic receptors, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising at least one compound of the formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and c; 
       A is selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       R is selected from H, C 1 -C 8  straight- or branched-chain alkyl or —CH 2 —P(O)(OH) 2 ; 
       a is —O—, —S— or —S(O)—; 
       b is —CR 1 R 2 — or —C(R 1 )═; 
       d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and —C═N(R 3 )═O; 
       e is selected from the group consisting of —CH 2 —, —CHR 4 —, —NH—, —NR 5 —, —N(SO 2 R 6 )— and —N(C(═O)R 6 )—; 
       R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  alkyl optionally substituted by one to three phenyls; 
       R 5  is selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, optionally substituted phenyl, heteroaryl, and C 1-6  alkyl optionally substituted by one to three phenyls; or, when the compound of formula (I) is a dimer, in which both halves of the dimer share a single R 5 , R 5  is selected from the group consisting of —(CH 2 ) n — and —(CH 2 O) n —, wherein n is 1 to 6; and 
       R 6  is selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-7  cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C 1-6  alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF 3  group, C 1-6  alkyl substituted by one to three aryl groups, and C m  alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C 1-6  alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl; 
       or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite, prodrug or pharmaceutically acceptable salt thereof, 
       with the proviso that when A is 
     
     
       
         
         
             
             
         
       
        R is —CH 3 , a is S, b is —CH(CH 2 CH 3 )— and d is —C(═O)—, then e is not —NH— (AF267) or an enantiomer thereof, and 
       with the further proviso that when A is 
     
     
       
         
         
             
             
         
       
        R is —CH 3 , a is S, b is —C(CH 3 )— and d is ═N—, then e is not —CH 2 — (AF150(S)). 
     
   
   
       132 . The method of  claim 131 , wherein said compound is selected from the group consisting of: (S)-2-Ethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF292), thia-4,8-diaza-spiro[4.5]decan-3-one; 4-(2,4-Dimethoxybenzyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF286); 8-Methyl-4-pyrrolidin-1-ylmethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF287); 2-(1-Hydroxy-ethyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF298); (S)-2-ethyl-8-methyl-3-oxo-1-thia-4,8-diaza-spiro[4,5]decane 8-oxide (AF299); 4-(2,4-Dimethoxy-benzyl)-2-ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF288); (S)-2-Ethyl-8-methyl-1-oxo-1λ 4 -thia-4,8-diaza-spiro[4.5]decan-3-one (AF300); 2-Ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decane-3-thione (AF510); (S)-2-Ethyl-4-(4-fluoro-benzenesulfonyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF700); 2-Ethyl-4-[2-(1H-indol-3-yl)-ethyl]-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF703); 2-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704); (S)-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704B); (R)-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704A); 2-Ethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF504), (S)-2-Ethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF292) and (R)-2-Ethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF291) or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, metabolite, prodrug or a pharmaceutically acceptable salt thereof. 
   
   
       133 . The method of  claim 131 , wherein said composition further comprises at least one additional pharmacologically active compound selected from the group consisting of cholinesterase inhibitors, nicotinic agonists, cholinergic precursors and cholinergic enhancers, nootropics, peripheral antimuscarine drugs, M2 muscarinic antagonists, M4 antagonists, benzodiapine inverse agonists, antidepressants, tricyclic antidepressants or antimuscarinic drugs used in treatment of Parkinson's disease (PD) or depression, antipsychotic and antischizophrenic agents, glutamate antagonists and modulators, NMDA antagonists, AMPA agonists, acetyl-L-carnitine, MAO-B inhibitors, peptides and growth factors, cholesterol-lowering agents, antioxidants, GSK-3p inhibitors, Wnt-ligands, P- or y-secretase inhibitors, beta-amyloid degrading agents, beta-amyloid anti-aggregation agents, cheating agents, immunotherapeutic compounds against beta-amyloids, compounds that bind to amyloids, cyclooxygenase (COX)-2 inhibitors, non-steroidal antiinflammatory drugs, estrogenic agents, estrogenic receptor modulators, steroidal neuroprotectants, and spin trapping pharmaceuticals. 
   
   
       134 . The method of  claim 131 , wherein said composition further comprises at least one additional compound selected from the group consisting of 2,8-Dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-2-ene (AF 150B) and (S)-2-ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF267B). 
   
   
       135 . The method of  claim 131 , wherein said disease or disorder is also associated with impaired cholinergic function or where there is an imbalance in cholinergic function, or with impaired activity of acetylcholine receptors, and wherein said disease or disorder is selected from the group consisting of senile dementia of Alzheimer's type; Alzheimer's disease (AD); Lewy body dementia; mixed Alzheimer's and Parkinson's disease; multiifract dementia (MID); fronto-temporal dementia; vascular dementia; stroke/ischemia, MID combined with stroke/ischemia/head injury; combined MID and AD; human head injury; age-associated memory impairments; mild cognitive impairment (MCI); MCI conducive to AD; cognitive dysfunction; hallucinatory-paranoid states; emotional and attention disorders; sleep disorders; postoperative delirium; adverse effects of tricyclic antidepressants; adverse effects of certain drugs used in the treatment of schizophrenia and Parkinson's disease; xerostomia, anomia, memory loss and/or confusion; psychosis; schizophrenia, schizophrenia comorbit with AD, late onset schizophrenia, paraphrenia, schizophreniform disorders; anxiety; bipolar disorders; mania; mood stabilization; cognitive impairments after removal of certain gliomas; tardive dyskinesia; oxidative stress during oxygen therapy; aphasia; postencephalitic amnesic syndrome; AIDS dementia; memory impairments in autoimmune diseases; memory impairments in atypical depression or schizophrenia; pain, rheumatism, arthritis and terminal illness; xerophtalmia, vaginal dryness, skin dryness; immune dysfunctions; neurocrine disorders and dysregulation of food intake, including bulimia and anorexia; obesity; congenital ornithine transcarbamylase deficiency; ollivopontocerebral atrophy; alcohol withdrawal symptoms; substance abuse; Huntington's chorea; progressive supranuclear palsy; Pick's disease; Friedrick's ataxia; Gilles de la Tourette disease; Down's syndrome: glaucoma; fronto-temporal dementia; vascular dementia; mild cognitive; anxiety; bipolar disorders; ollivopontocerebral atrophy; presbyopia; autonomic disorders; urinary urge incontinence, asthma and COPD. 
   
   
       136 . The method of  claim 131 , wherein said disease or disorder is associated with dysfunction in one or more of the following:
 brain, nervous system, cardiovascular system, immune system, neurocrine system, gastrointestinal system, endocrine and exocrine glands, eye, cornea, lungs, prostate, or other organs where the cholinergic function is mediated by muscarinic receptor subtypes, wherein said dysfunction involves brain amyloid-mediated disorders; glycogen synthase kinase (GSK3p)-mediated disorders; tau protein hyperphosphorylation-mediated damages, dysfunctions or diseases; CNS and PNS hypercholesterolemia- and/or hyperlipidemia-mediated damages, dysfunctions or diseases; Wnt-mediated signaling abnormalities; impairment of neuroplasticity; hyperglycemia; diabetes; endogenous growth factors-mediated diseases, or combination of additional risk factors; or disease states that involve apolipoprotein E; or disturbances in which a cholinergic dysfunction has been implicated, and   wherein said disease or disorder is selected from the group consisting of senile dementia of Alzheimer's type; Alzheimer's disease (AD); delay of onset of AD symptoms in a patient at risk for developing AD; Lewy body dementia; cerebral amyloid angiopathy (CAA); cerebral amyloidosis; fronto-temporal dementia; vascular dementia; hyperlipidemia; hypercholesterolemia; multiifract dementia (MID; stroke ischemia; MID combined with stroke/ischemia/head injury; combined MID and Alzheimer's disease; human head injury; age-associated memory impairments; mild cognitive impairment (MCI); MCI conducive to AD; bipolar disorder; mania; schizophrenia; nonaffective sychozophrenia; paraphrenia; immune dysfunctions; neurocrine disorders and dysregulation of food intake.   
   
   
       137 . The method of  claim 131  wherein said compound of formula (I) is AF792 or a pharmaceutically acceptable salt thereof. 
   
   
       138 . The method of  claim 133  wherein said compound of formula (I) is AF292 or a pharmaceutically acceptable salt thereof. 
   
   
       139 . The method of  claim 134  wherein said compound of formula (I) is AF292 or a pharmaceutically acceptable salt thereof. 
   
   
       140 . The method of  claim 135  wherein said compound of formula (I) is AF292 or a pharmaceutically acceptable salt thereof. 
   
   
       141 . The method of  claim 136  wherein said compound of formula (I) is AF292 or a pharmaceutically acceptable salt thereof. 
   
   
       142 . A method for achieving one or more of the following biological effects:
 (1) inhibiting the release or synthesis of beta-amyloid peptide Aβ in a mammalian cell, tissue or organism,   (2) elevating the level of secreted form of the non-amyloidogenic amyloid precursor protein,   (3) decreasing the level of Aβ peptide in the brain of a mammal having an elevated level of Aβ in the brain,   (4) decreasing level of or inhibiting the release or synthesis of Apolipoprotein in a mammalian cell, tissue or organism,   (5) decreasing tau hyperphosphorylation in a mammalian cell, tissue or organism,   (6) stimulating the M1 muscarinic receptor and activating α-secretase,   (7) stimulating the M1 muscarinic receptor and antagonizing one of more of β-secretase, γ-secretase, or M3-muscarinic receptor,   (8) decreasing paired helical formation in a mammalian cell,   (9) activating the Wnt signaling pathway in a mammalian cell, tissue or organism,   (10) enhancing the activity of endogenous growth factors,   (11) inhibiting GSK3β-mediated effects in a mammal or   (12) treating or reducing cerebral amyloid angiopathy,
 said method comprising administering to a system or subject in need thereof an effective amount of a pharmaceutical composition comprising a compound or a mixture of compounds selected from the group consisting of compounds according to formula (I), AF267B and AF150 (S), or racemates, enantiomers, geometrical isomers, diasteromers, tautomers and pharmaceutically acceptable salts thereof. 
   
   
   
       143 . The method according to  claim 142 , wherein said compound of formula (I) is AF292. 
   
   
       144 . A method of preventing or treating xerostomia, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising AF267B and at least one pharmaceutically acceptable carrier, diluent or excipient. 
   
   
       145 . A method of preventing or treating impairment associated with schizophrenia, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising AF267-B and at least one pharmaceutically acceptable carrier, diluent or excipient. 
   
   
       146 . A compound of the formula (II): 
     
       
         
         
             
             
         
       
       wherein: 
       C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and e; 
       A is selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       
         wherein the bridgehead nitrogen is optionally oxidized to form an N-oxide, R is selected from H, O, C 1 -C 8  straight- or branched-chain alkyl, or —CH 2 —P(═O)(OH) 2 ; 
       
       a is —O—, —S— or —S(O)—; 
       b is —CR 1 R 2 — or —C(R 1 )=; 
       d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and —C═N(R 3 )═O; 
       e is selected from the group consisting of —CH 2 —, —CHR 4 —, —NH—, —NR 5 —, —N(SO 2 R 6 )— and —N(C(═O)R 6 )—; 
       R 1 , R 2 , R 3  and R 4  are each independently selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  alkyl optionally substituted by one to three phenyls; 
       R 5  is selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, optionally substituted phenyl, heteroaryl, and C 1-6  alkyl optionally substituted by one to three phenyls; or, when the compound of formula (II) is a dimer, in which both halves of the dimer share a single R 1 , R 5  is selected from the group consisting of —CH 2 ) n — and —CH 2 O) n — wherein n is 1 to 6; and 
       R 6  is selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-7  cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C 1-6  alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF 3  group, C 1-6  alkyl substituted by one to three aryl groups, and C . . . alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C 1-6  alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl; 
       or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite or pharmaceutically acceptable salt thereof, 
       with the proviso that when A is 
     
     
       
         
         
             
             
         
       
        R is —H or —CH 3 , a is S, b is —CH(CH CH 3 )— and d is —C(═O)—, then e is not —NR 5 —, and 
       with the further proviso that when A is 
     
     
       
         
         
             
             
         
       
        R is —CH 3 , a is S, b is —C(CH 3 )═ and d is ═N—, then e is not —CH 2 — (AF150(S)). 
     
   
   
       147 . The compound of  claim 146 , wherein said compound is selected from the group consisting of, thia-4,8-diaza-spiro[4.5]decan-3-one; 4-benzyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF282); 4-(2,4-Dimethoxybenzyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF286); 8-Methyl-4-pyrrolidin-1-ylmethyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF287); 2-(1-Hydroxy-ethyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF298); (S)-2-Ethyl-8-methyl-8-oxy-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF299); 4-(2,4-Dimethoxy-benzyl)-2-ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF288); (S)-2-Ethyl-8-methyl-1-oxo-1λ 4 -thia-4,8-diaza-spiro[4.5]decan-3-one (AF300); 2-Ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-thione (AF510); (S)-2-Ethyl-4-(4-fluoro-benzenesulfonyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF700); 2-Ethyl-4-[2-(1H-indol-3-yl)-ethyl]-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF703); 2-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704); (S)-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704B); 4-(tert-Butyloxycarbonyl)-8-methyl-1-thia-4,8-diaza-spiro[4,5]decan-3-one (AF284); 2-Methyl-1-thia-3,8-diaza-spiro[4.5]dec-2-ene (AF400); 2,8-Dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-2-ene-8-oxide (AF406); N-[(2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-ylidene)-methyl-amine]-N-oxide (AF600); N-[(2-Ethyl-8-methyl-1-oxa-8-aza-spiro[4.5]dec-3-ylidene)-methyl-amine]-N-oxide (AF601); N-[(2-Methyl-8-phenyl-1-oxa-8-aza-spiro[4.5]dec-3-ylidene)-methyl-amine]-N-oxide (AF602); Dihydro-5′-methylspiro[1-azabicyclo[2.2.2]octane-3,5′-(4′H)-3′-ylidene-methylamine]-N-oxide (AF603); N-[(2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-ylidene)-benzyl-amine]-N-oxide (AF604); N-[(2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-ylidene)-isopropyl-amine]-N-oxide (AF605) and (R)-Ethyl-4-(3-1H-indol-3-yl-propionyl)-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF704A) or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, metabolite, or a pharmaceutically acceptable salt thereof. 
   
   
       148 . The compound of  claim 146  wherein
 a is —O—;   b is —CR 1 R 2 —;   d is —C═N(R 3 )═O;   e is —CH 2 —; and   R 1 , R 2  and R 3  are each independently selected from the group consisting of H C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  alkyl optionally substituted by one to three phenyls.   
   
   
       149 . The compound of  claim 146  wherein
 a is —S— or —S(O)—;   b is —CR 1 R 2 —;   d is selected from the group consisting of —C(═O)— and —C(═S)—;   e is selected from the group consisting of —NH—, —NR 5 —, —N(SO 2 R 6 )— and —N(C(═O)R 6 )—;   R 1  and R 2  are each independently selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C2-alkenyl, C 2-6  alkynyl, and C 1 -(alkyl optionally substituted by one to three phenyls;   R 5  is selected from the group consisting of H, C 1-6  alkoxy, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, optionally substituted phenyl, heteroaryl, and C 1-6  alkyl optionally substituted by one, two or three phenyls; or, when the compound of formula (II) is a dimer, in which both halves of the dimer share a single R 5 R 5  is selected from the group consisting of —CH 2 ) n — and —(CH 2 O) n — wherein n is 1 to 6; and   R 6  is selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  hydroxyalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-7  cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C 1-6  alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF 3  group, C 1-6  alkyl substituted by one to three aryl groups, and C m  alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C 1-6  alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl,   with the proviso that when A is   
     
       
         
         
             
             
         
       
        R is —H or —CH 3 , a is S, b is —CH(CH 2 CH 3 )— and d is —C(═O)—, then e is not —NR 5 —. 
     
   
   
       150 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 146 , or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite or pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, diluent or excipient therefor.